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1
Kam, Caleb M., Amanda L. Tauber, Stephan M. Levonis, and Stephanie S. Schweiker. "Design, synthesis and evaluation of potential inhibitors for poly(ADP-ribose) polymerase members 1 and 14." Future Medicinal Chemistry 12, no. 24 (December 2020): 2179–90. http://dx.doi.org/10.4155/fmc-2020-0218.
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Poly(ADP-ribose) polymerase (PARP) members PARP1 and PARP14 belong to an 18-member superfamily of post-translational modifying enzymes. A library of 9 novel non-NAD analog amine compounds was designed, synthesized and evaluated for inhibitory activity against PARP1 and PARP14. Both in silico studies and in vitro assays identified compound 2 as a potential PARP1 inhibitor, inhibiting activity by 93 ± 2% (PARP14 inhibition: 0 ± 6%), and 7 as a potential PARP14 inhibitor, inhibiting activity by 91 ± 2% (PARP1 inhibition: 18 ± 4%), at 10-μm concentration. Key in silico interactions with TYR907 in PARP1 and TYR1620 and TYR1646 in PARP14 have been identified. Compound 2 and compound 7 have been identified as potential leads for the development of selective PARP inhibitors.
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Maluchenko, Natalya, Darya Koshkina, Anna Korovina, Vasily Studitsky, and Alexey Feofanov. "Interactions of PARP1 Inhibitors with PARP1-Nucleosome Complexes." Cells 11, no. 21 (October 23, 2022): 3343. http://dx.doi.org/10.3390/cells11213343.
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Inhibitors (PARPi) of poly(ADP-ribose-)polymerase-1 (PARP1) are used in antitumor therapy; their cytotoxicity correlates with the efficiency of PARP1 trapping in cell chromatin. Previous studies have demonstrated the PARPi-induced trapping of PARP1 on DNA, although details of the mechanism remain controversial. Here, the interactions of PARP1-nucleosome complexes with PARPi, olaparib (Ola), talazoparib (Tala), and veliparib (Veli) were studied. PARPi trap PARP1 on nucleosomes without affecting the structure of PARP1-nucleosome complexes. The efficiency of PARP1 trapping on nucleosomes increases in the order of Tala>Ola>>Veli, recapitulating the relative trapping efficiencies of PARPi in cells, but different from the relative potency of PARPi to inhibit the catalytic activity of PARP1. The efficiency of PARP1 trapping on nucleosomes correlates with the level of inhibition of auto-PARylation, which otherwise promotes the dissociation of PARP1-nucleosome complexes. The trapping efficiencies of Tala and Ola (but not Veli) are additionally modulated by the enhanced PARP1 binding to nucleosomes. The dissociation of PARP1-nucleosome complexes occurs without a loss of histones and leads to the restoration of the intact structure of nucleosomal DNA. The data suggest that the chromatin structure can considerably affect the efficiency of the PARPi action.
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Zientara-Rytter, Kasia, Veronique T. Baron, Junguk Park, Pavel Shashkin, and Henry Zhu. "Abstract 6111: Design of a small molecule screening assay to detect DNA trapping of PARP1/2." Cancer Research 83, no. 7_Supplement (April 4, 2023): 6111. http://dx.doi.org/10.1158/1538-7445.am2023-6111.
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Abstract Poly(ADP-ribose) polymerase (PARP) inhibitors are currently used in the clinic for the treatment of tumors with a defective DNA damage response (DDR). When PARP1 or PARP2 binds damaged DNA, it adds poly(ADP-ribose) chains to its own backbone and to other DDR proteins, which recruits and activates them. PARylated PARP1/2 next detaches from the DNA so that the other PARylated proteins can initiate the repair process. It has been observed that some PARP inhibitors prevent PARP1/2 from dissociating the DNA. The continuous presence of PARP at the site of damage prevents repair and blocks replication, leading to cell death. Therefore, drugs that trap PARP1/2 to the DNA tend to be significantly more cytotoxic than other PARP inhibitors, which is highly desirable. This study describes the design and optimization of novel PARPtrap assays to specifically assess the ability of a drug to trap PARP onto DNA. The assay is based on principles of fluorescence polarization and uses fluorescently labeled DNA probes that are excited by polarized light and emit light with a degree of polarization that is proportional to the rate of molecular rotation. The free DNA probes that rotate fast have low fluorescence polarization (FP), but high FP when are bound to PARP1 or PARP2. When NAD+ is added, the PARylated enzymes detach from the probe, reducing FP levels. If a PARP inhibitor is added, the inhibitor’s trapping ability increases FP in a dose-dependent manner. Proof-of-principle titration of known PARP-trapping inhibitors (Talazoparib, AZD305, Olaparib and Veliparib) was performed to validate the assay. We observed that: i)The known relative trapping efficacies of Talazoparib, Olaparib and Veliparib were similar to known relative efficacies. ii)Talazoparib, Olaparib and Veliparib had similar trapping efficacy against PARP1 and PARP2, as measured by their EC50, whereas AZD305 was 1,000 times more efficient at trapping PARP1 than it was PARP2, demonstrating selectivity between PARP1 and PARP2. iii)AZD305 displayed as efficient DNA trapping activity toward PARP1 as best-in-class Talazoparib. In summary, we have designed an innovative PARPtrap assay designed for the high throughput screening of small molecule libraries to specifically identify or compare inhibitors that are capable of trapping PARP1 and/or PARP2 onto DNA. Citation Format: Kasia Zientara-Rytter, Veronique T. Baron, Junguk Park, Pavel Shashkin, Henry Zhu. Design of a small molecule screening assay to detect DNA trapping of PARP1/2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6111.
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Ji, Ming, Liyuan Wang, Nina Xue, Fangfang Lai, Sen Zhang, Jing Jin, and Xiaoguang Chen. "The Development of a Biotinylated NAD+-Applied Human Poly(ADP-Ribose) Polymerase 3 (PARP3) Enzymatic Assay." SLAS DISCOVERY: Advancing the Science of Drug Discovery 23, no. 6 (April 20, 2018): 545–53. http://dx.doi.org/10.1177/2472555218767843.
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Poly(ADP-ribose) polymerase 3 (PARP3) is an important member of the PARP family and shares high structural similarities with both PARP1 and PARP2. The biological roles of PARP3 are currently under investigation; however, several key reports indicate the integral roles of PARP3 in DNA damage repair, and thus it has been investigated as a novel target in oncology. It is clear that the identification of selective PARP3 inhibitors would further advance the understanding of the biological roles of PARP3. Herein, we describe a modified PARP3 screening assay using biotinylated NAD+ as the specialized substrate. This method relies on the activity of PARP3 to transfer the biotinylated NAD+ onto a histone protein to form ADP-ribosylated histone. The biotin label on this histone protein is then detected and quantifies the intrinsic enzymatic activity of PARP3. We optimized the assay with respect to the histone, NAD+/biotinylated NAD+ mixture, DNA, and PARP3. Our developed screening system was then validated with a reported selective PARP3 inhibitor, ME0328, as well as utilizing five other clinically available PARP1/2 inhibitors. We demonstrated that our assay system was sensitive, efficient, and economical, and we reason that it could be useful for the development of highly selective PARP3 inhibitors in the future.
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Halazonetis, Thanos D., Michalis Petropoulos, Giacomo G. Rossetti, Angeliki Karamichali, Alena Freudenmann, Luca Iacovino, Vasilis Dionellis, and Sotirios K. Sotiriou. "Abstract 1566: DNA damage generated by transcription-replication conflicts explains the synthetic lethality of PARP inhibitors with homologous recombination deficiency." Cancer Research 83, no. 7_Supplement (April 4, 2023): 1566. http://dx.doi.org/10.1158/1538-7445.am2023-1566.
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Abstract An important advance in cancer therapy in the last decade has been the development of poly ADP-ribose polymerase (PARP) inhibitors for the treatment of select ovarian and breast cancers. The clinical benefit stems from the synthetic lethality of PARP inhibitors with homologous recombination (HR) deficiency, which deficiency is prevalent in the cancer types listed above. The current model to explain the synthetic lethality is based on the observation that PARP inhibitors trap PARPs on DNA: the trapped PARPs block progression of the replisome, leading to the formation of DNA double-strand breaks (DSBs), which require HR for repair. Here, we propose a novel mechanism to explain the synthetic lethality between PARP inhibitors and HR deficiencies. We show that PARP1 functions together with the proteins TIMELESS and TIPIN to protect the replisome from transcription-replication conflicts (TRCs). In the absence of any one of these proteins, TRCs evolved into DNA DSBs that required HR for repair, explaining the observed synthetic lethality. In further support of this model, when we inhibited transcription elongation, which prevents the emergence of transcription-replication conflicts, then the HR-deficient cancer cells became resistant to PARP inhibitors. We further observed that trapping of PARPs on DNA was not required for the synthetic lethality with HR deficiency, since we could observe strong synthetic lethality simply by depleting PARP1 and PARP2 by siRNA. Rather, trapping of PARPs on DNA correlated with the ability of the various PARP inhibitors to inhibit PARP enzymatic activity in cells; the strongest trappers were also the most potent inhibitors of PARP1 in cells. In vitro, all PARP inhibitors tested were almost equipotent in their ability to inhibit the enzymatic activity of PARP1, meaning that the potency of PARP1 inhibitors in vitro did not reflect their inhibitory potency in cells. Our model provides a new framework for understanding the mechanism of action of PARP inhibitors in the clinic and the mechanisms by which resistance can emerge. Citation Format: Thanos D. Halazonetis, Michalis Petropoulos, Giacomo G. Rossetti, Angeliki Karamichali, Alena Freudenmann, Luca Iacovino, Vasilis Dionellis, Sotirios K. Sotiriou. DNA damage generated by transcription-replication conflicts explains the synthetic lethality of PARP inhibitors with homologous recombination deficiency [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1566.
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Wang, Kai, Yizhou Wu, Lizhu Lai, Xin Wang, and Shuya Sun. "How ligands regulate the binding of PARP1 with DNA: Deciphering the mechanism at the molecular level." PLOS ONE 18, no. 8 (August 15, 2023): e0290176. http://dx.doi.org/10.1371/journal.pone.0290176.
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The catalytic (CAT) domain is a key region of poly (ADP-ribose) polymerase 1 (PARP1), which has crucial interactions with inhibitors, DNA, and other domains of PARP1. To facilitate the development of potential inhibitors of PARP1, it is of great significance to clarify the differences in structural dynamics and key residues between CAT/inhibitors and DNA/PARP1/inhibitors through structure-based computational design. In this paper, conformational changes in PAPR1 and differences in key residue interactions induced by inhibitors were revealed at the molecular level by comparative molecular dynamics (MD) simulations and energy decomposition. On one hand, PARP1 inhibitors indirectly change some residues of the CAT domain which interact with DNA and other domains. Furthermore, the interaction between ligands and catalytic binding sites can be transferred to the DNA recognition domain of PARP1 by a strong negative correlation movement among multi-domains of PARP1. On the other hand, it is not reliable to use the binding energy of CAT/ligand as a measure of ligand activity, because it may in some cases differs greatly from the that of PARP1/DNA/ligand. For PARP1/DNA/ligand, the stronger the binding stability between the ligand and PARP1, the stronger the binding stability between PARP1 and DNA. The findings of this work can guide further novel inhibitor design and the structural modification of PARP1 through structure-based computational design.
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Yin, Ling, and Junjie Chen. "Abstract 6098: Genome wide CRISPR screen reveals genetic vulnerabilities of next generation PARP1 inhibitor AZD5305." Cancer Research 83, no. 7_Supplement (April 4, 2023): 6098. http://dx.doi.org/10.1158/1538-7445.am2023-6098.
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Abstract The first-generation PARP inhibitors (PARPi) olaparib, niraparib, talazoparib and rucaparib have been clinically approved for several cancers, like breast, ovarian and prostate, especially in BRCA-mutant tumors which are of homologous recombination repair (HRR)-deficiency. All PARPi both target PARP1 and PARP2, causing cancer cell deaths deficient in HRR. However, only inhibition of PARP1 is required for synthetic lethality in HRR-deficient cells. AZD5305 is a highly selective PARP1 inhibitor which has been used in clinical trials. In this study, we used the Toronto Knock Out Library version 3 (TKOv3), which contains 70948 gRNAs targeting 18,053 protein-coding genes to perform whole-genome CRISPR-Cas9 screens with three isogenic cell lines 293A, MCF10A, and Hela to uncover known and new high-confidence genes synthetic lethal interacted with AZD5305. MAGeCK and Drug Z were used to analyze the results and genes were ranked according to their drugZ scores. We identify that in all three cell lines, PARP1 was in the top hit in positive selection which proves the AZD5305 indeed a PARP1 inhibitor. Moreover, through a comprehensive and comparative analysis with the screen results of first generation PARPi olaparib, we reveal known and new essential genes which are proved to be a common mechanism for synthetic lethality. We identify the gene AUNIP (Aurora Kinase A and Ninein Interacting Protein), in the top hit from AZD5305 screen but not in olaparib screen, suggesting that AUNIP may be an additional target for synthetic lethality with PARP1 loss. Taken together, this screen reveals the potential molecular genes related with PARP1 inhibitor that can be further explored targeted and combined cancer therapy. Citation Format: Ling Yin, Junjie Chen. Genome wide CRISPR screen reveals genetic vulnerabilities of next generation PARP1 inhibitor AZD5305 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6098.
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Krastev, Dragomir B., Andrew J. Wicks, and Christopher J. Lord. "PARP Inhibitors – Trapped in a Toxic Love Affair." Cancer Research 81, no. 22 (November 15, 2021): 5605–7. http://dx.doi.org/10.1158/0008-5472.can-21-3201.
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Abstract It is often the case that when an investigational cancer drug first enters clinical development, its precise mechanism of action is unclear. This was the case for PARP inhibitors (PARPi) used to treat homologous recombination–defective cancers. In 2012, nearly a decade after the first PARPi entered clinical development, work from Murai and colleagues demonstrated that clinical PARPi not only inhibit the catalytic activity of PARP1, PARylation, but also “trap” PARP1 on DNA; this latter effect being responsible for much of the tumor cell cytotoxicity caused by these drugs. We discuss how this work not only changed our understanding about how PARPi work, but also stimulated subsequent dissection of how PARP1 carries out its normal function in the absence of inhibitor. See related article by Murai and colleagues, Cancer Res 2012;72:5588–99
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Nieborowska-Skorska, Margaret, Paulina Podszywalow-Bartnicka, Silvia Maifrede, Bac Viet Le, Monika Toma, Peter Valent, Tomasz Sliwinski, et al. "PARP1 Inhibitors Eliminated Imatinib-Refractory Chronic Myeloid Leukemia Cells in Bone Marrow Microenvironment Conditions." Blood 132, Supplement 1 (November 29, 2018): 3000. http://dx.doi.org/10.1182/blood-2018-99-115041.
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Abstract Bone marrow microenvironment (BMM) also defined as a stem cell niche provides a major obstacle for current anti-leukemia treatment modalities including tyrosine kinase inhibitors (TKIs) such as imatinib. We recently reported that chronic myeloid leukemia (CML) stem cells are sensitive to PARP inhibitor (PARPi)-triggered synthetic lethality in conditions mimicking peripheral blood (normoxia, no stromal cells). We reported that PARPi olaparib and talazoparib eliminate imatinib-refractory CML cells in the conditions mimicking BMM (hypoxia, stromal cells present). The effect, however, is not as robust as that observed in normoxia implicating BMM-specific protective impact. Therefore, more efficient targeting of PARP is required to enhance synthetic lethal effect against CML in BMM. Most PARPi's have been designed to compete with NAD for a binding site on the PARP1 molecule. This strategy resulted in the discovery of nucleotide-like PARPi's that not only target PARP, but, unfortunately, other enzymatic pathways involving NAD and other nucleotides as co-factors. Using such inhibitors affects multiple NAD/nucleotide-dependent enzymatic pathways, which results in secondary toxic effects proceeding from the inactivation of other pathways, while the efficiency against the PARP pathway is diminished. Thus, the challenge is to design inhibitors based on other activities of PARP1. We reported that DSBs-dependent interaction of PARP1 with histone 4 (H4) resulted in activation of PARP1 enzymatic activity and stimulation of Alt-NHEJ. Using high-throughput screen we identified non-NAD-like inhibitors, which interfered with H4-mediated activation of PARP1 and were effective against several types of tumors including BRCA1-deficient CML cells. Here we show that combination of two structurally different PARPi's, NAD-like olaparib or talazoparib and non-NAD-like 5F02 resulted in more abundant elimination of CML cells and reduced toxicity to normal counterparts. Finally, the combination exerted synergistic effect in humanized immunodeficient mice bearing primary CML xenografts. Altogether, non-NAD-like PARP1i synergistically enhanced synthetic lethal effect of NAD-like PARPi in tumor cells without increasing the cytotoxic effect in normal cells. While synthetic lethality mediated by NAD-like PARPi is usually associated with enhanced accumulation of potentially lethal DSBs, non-NAD-like PARP1i 5F02 did not induce DSBs when used as a single agent and also in combination with olaparib. Thus, the mechanistic aspect of the synergistic effect of NAD-like and non-NAD-like PARPis needs to be elucidated. Nevertheless, our data suggest that combining NAD-like and allosteric non-NAD-like PARPi's may represent a viable therapeutic strategy for enhancing CML response to PARP inhibition and reducing the resistance that inevitably results from treatment with NAD-like PARPi's alone. Disclosures Valent: Novartis: Honoraria; Incyte: Honoraria; Pfizer: Honoraria.
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Tutt, Andrew. "Abstract ED12-3: ATR inhibitors and PARP1 selective PARP inhibitors." Cancer Research 83, no. 5_Supplement (March 1, 2023): ED12–3—ED12–3. http://dx.doi.org/10.1158/1538-7445.sabcs22-ed12-3.
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Abstract The targeting of Homologous Recombination deficient (HRD) malignancy using a synthetic lethal strategy based on the inhibition and trapping of PARP1 on DNA in manner that leads to tumour selective effects via dependency on the function of HR gene products such as BRCA1, BRCA2 and PALB2 for DNA replication fitness is now well established. However, there is a need to improve both the frequency and duration of response in the licensed indications and to explore combination PARP inhibitor (PARPi) strategies that may be effective a broader range of breast cancers with functional deficiencies in HR and the wider DNA damage response. ATR inhibitors exacerbate replication stress that is toxic to HR deficient cells. Combinations of an ATR inhibition (ATRi) and PARPi have been shown to be synergistic and to be active in PARPi resistant pre-clinical model contexts. The development of combination strategies of these agents and of platinums and ATRi have been limited by combinatorial toxicity but have recently reported results in breast cancer. PARP1 is part of a family of PARP enzymes and currently licensed PARPi inhibit several family members that underpin some of their toxicity. New PARP1 selective agents have recently reported results in early phase trials. I will review some of the mechanistic rationale, preclinical data and relevant clinical trial data in my lecture. Citation Format: Andrew Tutt. ATR inhibitors and PARP1 selective PARP inhibitors [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr ED12-3.
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Demény, Máté A., and László Virág. "The PARP Enzyme Family and the Hallmarks of Cancer Part 1. Cell Intrinsic Hallmarks." Cancers 13, no. 9 (April 23, 2021): 2042. http://dx.doi.org/10.3390/cancers13092042.
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The 17-member poly (ADP-ribose) polymerase enzyme family, also known as the ADP-ribosyl transferase diphtheria toxin-like (ARTD) enzyme family, contains DNA damage-responsive and nonresponsive members. Only PARP1, 2, 5a, and 5b are capable of modifying their targets with poly ADP-ribose (PAR) polymers; the other PARP family members function as mono-ADP-ribosyl transferases. In the last decade, PARP1 has taken center stage in oncology treatments. New PARP inhibitors (PARPi) have been introduced for the targeted treatment of breast cancer 1 or 2 (BRCA1/2)-deficient ovarian and breast cancers, and this novel therapy represents the prototype of the synthetic lethality paradigm. Much less attention has been paid to other PARPs and their potential roles in cancer biology. In this review, we summarize the roles played by all PARP enzyme family members in six intrinsic hallmarks of cancer: uncontrolled proliferation, evasion of growth suppressors, cell death resistance, genome instability, reprogrammed energy metabolism, and escape from replicative senescence. In a companion paper, we will discuss the roles of PARP enzymes in cancer hallmarks related to cancer-host interactions, including angiogenesis, invasion and metastasis, evasion of the anticancer immune response, and tumor-promoting inflammation. While PARP1 is clearly involved in all ten cancer hallmarks, an increasing body of evidence supports the role of other PARPs in modifying these cancer hallmarks (e.g., PARP5a and 5b in replicative immortality and PARP2 in cancer metabolism). We also highlight controversies, open questions, and discuss prospects of recent developments related to the wide range of roles played by PARPs in cancer biology. Some of the summarized findings may explain resistance to PARPi therapy or highlight novel biological roles of PARPs that can be therapeutically exploited in novel anticancer treatment paradigms.
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Shao, Zhengping, Brian J. Lee, Élise Rouleau-Turcotte, Marie-France Langelier, Xiaohui Lin, Verna M. Estes, John M. Pascal, and Shan Zha. "Clinical PARP inhibitors do not abrogate PARP1 exchange at DNA damage sites in vivo." Nucleic Acids Research 48, no. 17 (September 5, 2020): 9694–709. http://dx.doi.org/10.1093/nar/gkaa718.
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Abstract DNA breaks recruit and activate PARP1/2, which deposit poly-ADP-ribose (PAR) to recruit XRCC1-Ligase3 and other repair factors to promote DNA repair. Clinical PARP inhibitors (PARPi) extend the lifetime of damage-induced PARP1/2 foci, referred to as ‘trapping’. To understand the molecular nature of ‘trapping’ in cells, we employed quantitative live-cell imaging and fluorescence recovery after photo-bleaching. Unexpectedly, we found that PARP1 exchanges rapidly at DNA damage sites even in the presence of clinical PARPi, suggesting the persistent foci are not caused by physical stalling. Loss of Xrcc1, a major downstream effector of PAR, also caused persistent PARP1 foci without affecting PARP1 exchange. Thus, we propose that the persistent PARP1 foci are formed by different PARP1 molecules that are continuously recruited to and exchanging at DNA lesions due to attenuated XRCC1-LIG3 recruitment and delayed DNA repair. Moreover, mutation analyses of the NAD+ interacting residues of PARP1 showed that PARP1 can be physically trapped at DNA damage sites, and identified H862 as a potential regulator for PARP1 exchange. PARP1-H862D, but not PARylation-deficient PARP1-E988K, formed stable PARP1 foci upon activation. Together, these findings uncovered the nature of persistent PARP1 foci and identified NAD+ interacting residues involved in the PARP1 exchange.
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Gao, Mingming, Zhentian Li, Qipeng Fan, Jun Pan, Yu Bai, Hewen Zhang, Yu Li, et al. "Abstract 1648: Discovery of a potent and selective PARP1 inhibitor and trapper with anti-tumor activities in HRD tumors." Cancer Research 83, no. 7_Supplement (April 4, 2023): 1648. http://dx.doi.org/10.1158/1538-7445.am2023-1648.
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Abstract PARP1/2 inhibitors are FDA approved for treatment of cancers such as ovarian, prostate, pancreas and breast with greatest activity against tumors harboring BRCA1 or 2 mutation or homologous recombination deficiency (HRD). A shared adverse event that contributes to a narrow therapeutic index and limits combination potential is hematologic toxicity. First generation PARP inhibitors are not selective against PARP2, which has been shown to play a role in the survival of hematopoietic progenitor cells in animal models. However genetic studies suggest that the synthetic lethality from PARP trapping with HRD is primarily dependent on PARP1. We hypothesized that a potent and selective PARP1 inhibitor and trapper would achieve equivalent anti-tumor activity as non-selective PARP inhibitors while alleviating toxicities caused by PARP2 inhibition. SNV-001 is a novel, proprietary, potent, and selective PARP1 inhibitor and trapper. In PARylation assays, SNV-001 inhibited PARP1 activity with low nanomolar potency and displayed greater than 500-fold selectivity against PARP2. In cellular PARP trapping assays, SNV-001 potently trapped PARP1 on DNA in a dose-dependent manner but did not trap PARP2 up to 25 µM. Functionally, SNV-001 exhibited selective growth inhibitory activity against cancer cell lines with impaired HR function. In anti-proliferation and colony formation assays of BRCA-mutant cell lines including MDA-MB-436 (BRCA1 deficient) and DLD1 (BRCA2 knockout), SNV-001 inhibited cell growth and colony formation with single-digit nM IC50 values while having minimal effects against BRCA-WT cells. In a subcutaneous MDA-MB-436 xenograft tumor model, SNV-001 administered orally once daily achieved dose-dependent inhibition of PARylation in vivo. Furthermore, SNV-001 showed dose-dependent tumor growth inhibition using low daily doses with greater efficacy compared to olaparib dosed at 100 mg/kg once daily. In the cohort receiving a higher dose of SNV-001, all animals showed complete regression after 35 days of treatment without any clinical signs of toxicity. In summary, we have discovered SNV-001, a potent and selective PARP1 inhibitor and trapper that shows excellent activity against cancer models with HRD in vitro and in vivo. These data support advancement of SNV-001 into clinical development for patients with tumors characterized by HRD. Citation Format: Mingming Gao, Zhentian Li, Qipeng Fan, Jun Pan, Yu Bai, Hewen Zhang, Yu Li, Yongzhong Wu, Phillip C.C. Liu, Liangxing Wu, Wenqing Yao, Hui Wang. Discovery of a potent and selective PARP1 inhibitor and trapper with anti-tumor activities in HRD tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1648.
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Nguyen, Nghia T., Anna Pacelli, Michael Nader, and Susanne Kossatz. "DNA Repair Enzyme Poly(ADP-Ribose) Polymerase 1/2 (PARP1/2)-Targeted Nuclear Imaging and Radiotherapy." Cancers 14, no. 5 (February 23, 2022): 1129. http://dx.doi.org/10.3390/cancers14051129.
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Since it was discovered that many tumor types are vulnerable to inhibition of the DNA repair machinery, research towards efficient and selective inhibitors has accelerated. Amongst other enzymes, poly(ADP-ribose)-polymerase 1 (PARP1) was identified as a key player in this process, which resulted in the development of selective PARP inhibitors (PARPi) as anti-cancer drugs. Most small molecule PARPi’s exhibit high affinity for both PARP1 and PARP2. PARPi are under clinical investigation for mono- and combination therapy in several cancer types and five PARPi are now clinically approved. In parallel, radiolabeled PARPi have emerged for non-invasive imaging of PARP1 expression. PARP imaging agents have been suggested as companion diagnostics, patient selection, and treatment monitoring tools to improve the outcome of PARPi therapy, but also as stand-alone diagnostics. We give a comprehensive overview over the preclinical development of PARP imaging agents, which are mostly based on the PARPi olaparib, rucaparib, and recently also talazoparib. We also report on the current status of clinical translation, which involves a growing number of early phase trials. Additionally, this work provides an insight into promising approaches of PARP-targeted radiotherapy based on Auger and α-emitting isotopes. Furthermore, the review covers synthetic strategies for PARP-targeted imaging and therapy agents that are compatible with large scale production and clinical translation.
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Chen, MeiKuang, Yuan Gao, Weiya Xia, Yu-Han Wang, Jennifer K. Litton, Yu-Yi Chu, Funda Meric-Bernstam, et al. "Abstract 1792: FGFR3 mediated PARP1 tyrosine 158 phosphorylation promotes PARP inhibitor resistance." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1792. http://dx.doi.org/10.1158/1538-7445.am2022-1792.
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Abstract Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi), which induce DNA damage by inhibiting PARP1 enzymatic activity and trapping PARP on the damaged DNA, are used to eliminate BRCA1/2-mutated (BRCAm) cancer. However, clinical observations suggest that BRCAm tumors develop PARPi resistance. Current strategies to overcome PARPi resistance include impeding multiple DNA repair pathways to induce excessive DNA damage. Here, we propose a novel strategy targeting oncogenic receptor tyrosine kinases to enhance PARP trapping. By developing triple-negative breast cancer (TNBC) cells with acquired talazoparib resistance, we observed a high prevalence of activated fibroblast growth factor receptor 3 (FGFR3) kinase in these cells through kinase antibody array analysis. Mass spectrometry analysis and in vitro kinase assay suggested that FGFR3 phosphorylated PARP1 at tyrosine residues 158 and 176. Biochemistry studies suggested that only PARP1 tyrosine 158 phosphorylation contributes to PARPi resistance in the cells we developed. We then developed a monoclonal antibody against tyrosine 158 phosphorylated PARP1, and found that high-level PARP1 tyrosine 158 phosphorylation positively correlated with PARPi resistance in breast cancer patient-derived xenograft models. We further demonstrated that the combination of FGFR inhibitor and PARPi delayed DNA repair with prolonged PARP trapping. Moreover, synergy between PARPi and FGFR inhibition was observed in multiple TNBC cell lines with PARPi resistance in vitro. The combination of PARPi and FGFR inhibitor also showed synergism in vivo, and treatment with the combination of PARPi and FGFR inhibitor was tolerated in mouse models. These findings reveal that PARP1 tyrosine 158 phosphorylation facilitates resolving of the PARPi-induced PARP-trapping, and that the tyrosine 158 phosphorylated PARP1 may be an effective biomarker to indicate FGFR3 mediated PARPi resistance. Citation Format: MeiKuang Chen, Yuan Gao, Weiya Xia, Yu-Han Wang, Jennifer K. Litton, Yu-Yi Chu, Funda Meric-Bernstam, Helen Piwnica-Worms, Banu Arun, Jordi Rodon Ahnert, Yongkun Wei, Wei-Chao Chang, Hung-Ling Wang, Coya Tapia, Constance T. Albarracin, Shao-Chun Wang, Ying-Nai Wang, Gabriel N. Hortobagyi, Chunru Lin, Liuqing Yang, Dihua Yu, Mien-Chie Hung. FGFR3 mediated PARP1 tyrosine 158 phosphorylation promotes PARP inhibitor resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1792.
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Nam, Sujin, Jiyoung Chae, Kyung-Ok Cho, Tae-Sung Koo, Jungho Kim, Myungeun Jung, Jeongmin Kim, and Eunhee Kim. "Abstract 509: DM5167, a novel selective PARP1 inhibitor, efficiently reduces growth of triple-negative breast cancers." Cancer Research 83, no. 7_Supplement (April 4, 2023): 509. http://dx.doi.org/10.1158/1538-7445.am2023-509.
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Abstract Poly (ADP-ribose) polymerase 1 (PARP1) has been portrayed as a synthetic lethal target in cancers with homologous recombination deficiency. As all four PARP inhibitors on the market target both PARP1 and PARP2 isotypes, hematological toxicity issue emerged by PARP2 inhibition. To address the unmet need, we screened and optimized compounds exempt from the toxicity issue. Here, we present DM5167 as a new molecular entity with 0.41 nM of IC50 on the catalytic activity of PARP1. In addition, DM5167 exhibits an inhibitory profile against various PARP isotypes that differs from the four commercial PARP inhibitors. Specifically, DM5167 shows selectivity for PARP1 6.88 and 347.83 fold greater than PARP2 in the in vitro enzyme assay and DNA trapping assay, respectively. This contrasts with the corresponding PARP1/PARP2 selectivity values of 0.14 and 0.89 fold for olaparib, respectively. Moreover, DM5167 showed higher selectivity than AZD5305 in the enzymatic assay. The GLP toxicity studies assigned DM5167 as a safe compound based on its high NoAEL value, a general toxicity parameter. In addition, the safety margin of DM5167 was acceptable, indicating that DM5167 is a plausible drug candidate. To find suitable indications, we screened various human cancer cell lines using their inhibitory potentials against proliferation and colony formation. Several hits were seen in triple-negative breast cancer cell lines including MDA-MB-231, MDA-MB-436, MDA-MB-468 and HCC1395. In an orthotopic xenograft experiment in which MDA-MB-231 cells were implanted, oral administration of 50mpk of DM5167 inhibited tumor growth by 45.8%. In contrast, olaparib failed to reduce xenograft tumors derived from MDA-MB-231 cells. Collectively, these studies present DM5167 as an attractive anti-TNBC drug candidate. Citation Format: Sujin Nam, Jiyoung Chae, Kyung-Ok Cho, Tae-Sung Koo, Jungho Kim, Myungeun Jung, Jeongmin Kim, Eunhee Kim. DM5167, a novel selective PARP1 inhibitor, efficiently reduces growth of triple-negative breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 509.
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Murai, Junko, Shar-yin N. Huang, Benu Brata Das, Amelie Renaud, Yiping Zhang, James H. Doroshow, Jiuping Ji, Shunichi Takeda, and Yves Pommier. "Trapping of PARP1 and PARP2 by Clinical PARP Inhibitors." Cancer Research 72, no. 21 (October 31, 2012): 5588–99. http://dx.doi.org/10.1158/0008-5472.can-12-2753.
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Ghosh, Avipsa, Sudhir M. Hande, Amber Balazs, Derek Barratt, Sabina Cosulich, Barry Davies, Sébastien Degorce, et al. "Abstract 6302: Structure-based and property-based drug design of AZD9574, a CNS penetrant PARP1 selective inhibitor and trapper." Cancer Research 82, no. 12_Supplement (June 15, 2022): 6302. http://dx.doi.org/10.1158/1538-7445.am2022-6302.
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Abstract PARP inhibitors exploit defects in DNA repair pathways to selectively target cancerous cells via PARP1 catalytic inhibition and PARP1 trapping onto the DNA. All known clinical PARP1 inhibitors bind at the same site at the catalytic center of the enzyme. However, despite this resemblance they show immensely different outcomes in terms of response rate in the clinic due to their varying degree of PARP trapping ability. Moreover, the first-generation PARP inhibitors were not optimized for selectivity across the PARP family potentially driving undesirable side effects, including intestinal toxicity from tankyrase inhibition or hematological toxicity from PARP2 inhibition. There has been strong rationale for the use of PARP inhibitors in neuro-oncology. However, the first-generation PARP inhibitors have limited CNS distribution as these drugs were not designed for brain penetration. Recently AstraZeneca has reported the discovery of AZD5305, a next generation PARP1 selective inhibitor and PARP1-DNA trapper which was not designed with a CNS penetrant profile. Given the unmet need of a brain penetrant PARP1 inhibitor, we set out to identify a highly potent and selective PARP1 inhibitor and trapper with CNS profile. In our next generation PARP1 inhibitor, we sought to retain the profile of AZD5305 and lower the efflux for CNS penetration. Despite the challenge of narrow SAR, we successfully used the structure- and property-based design approach to identify a brain penetrant PARP1 inhibitor and PARP1-DNA trapper. We used multiple medicinal chemistry maneuvers such as masking the hydrogen bond donors and core modifications to lower the efflux in order to achieve brain penetration. Further optimization of the nicotinamide mimetic core for potency and metabolic stability led us to the discovery of AZD9574.AZD9574 shows improved selectivity for PARP1 over PARP2 vs AZD5305 and retains its excellent selectivity over other PARP family members. It has low efflux in Caco2, MDCK-MDR1, and MDCK-MDR1-BCRP permeability assays and it also showed CNS penetration in rat and cynomolgus monkey. AZD9574 has excellent secondary pharmacology and acceptable physicochemical properties and good PK in preclinical species.In vitro, AZD9574 selectively inhibits the growth of BRCAm cell lines. Importantly, AZD9574 showed efficacy in an intracranial BRCA1m MDA-MB-436 xenograft model at doses of 3, 10 and 30 mg/kg QD, significantly extending the survival of tumor-bearing mice compared to vehicle control arm.In summary, AZD9574 is a next generation selective PARP1 inhibitor and trapper with CNS penetration. This profile makes it an ideal candidate for treating CNS malignancies or brain metastases that have a dependence on PARP inhibition either as single agent or in combination with other therapies. Citation Format: Avipsa Ghosh, Sudhir M. Hande, Amber Balazs, Derek Barratt, Sabina Cosulich, Barry Davies, Sébastien Degorce, Kevin Embrey, Sonja Gill, Anders Gunnarsson, Giuditta Illuzzi, Peter Johnström, Jordan Lane, Carrie Larner, Rachel Lawrence, Elisabetta Leo, Andrew Madin, Elizabeth Martin, Lisa McWilliams, Lenka O’Connor, Mark O’Connor, Jonathan Orme, Fiona Pachl, Martin Packer, Andy Pike, Philip Rawlins, Marianne Schimpl, Magnus Schou, Anna Staniszewska, Wenzhan Yang, James Yates, Andrew Zhang, XiaoLa Zheng, Stephen Fawell, Petra Hamerlik, Jeffrey Johannes. Structure-based and property-based drug design of AZD9574, a CNS penetrant PARP1 selective inhibitor and trapper [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6302.
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Csizmar, Clifford M., Antoine N. Saliba, Elizabeth M. Swisher, and Scott H. Kaufmann. "PARP Inhibitors and Myeloid Neoplasms: A Double-Edged Sword." Cancers 13, no. 24 (December 20, 2021): 6385. http://dx.doi.org/10.3390/cancers13246385.
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Despite recent discoveries and therapeutic advances in aggressive myeloid neoplasms, there remains a pressing need for improved therapies. For instance, in acute myeloid leukemia (AML), while most patients achieve a complete remission with conventional chemotherapy or the combination of a hypomethylating agent and venetoclax, de novo or acquired drug resistance often presents an insurmountable challenge, especially in older patients. Poly(ADP-ribose) polymerase (PARP) enzymes, PARP1 and PARP2, are involved in detecting DNA damage and repairing it through multiple pathways, including base excision repair, single-strand break repair, and double-strand break repair. In the context of AML, PARP inhibitors (PARPi) could potentially exploit the frequently dysfunctional DNA repair pathways that, similar to deficiencies in homologous recombination in BRCA-mutant disease, set the stage for cell killing. PARPi appear to be especially effective in AML with certain gene rearrangements and molecular characteristics (RUNX1-RUNX1T1 and PML-RARA fusions, FLT3- and IDH1-mutated). In addition, PARPi can enhance the efficacy of other agents, particularly alkylating agents, TOP1 poisons, and hypomethylating agents, that induce lesions ordinarily repaired via PARP1-dependent mechanisms. Conversely, emerging reports suggest that long-term treatment with PARPi for solid tumors is associated with an increased incidence of myelodysplastic syndrome (MDS) and AML. Here, we (i) review the pre-clinical and clinical data on the role of PARPi, specifically olaparib, talazoparib, and veliparib, in aggressive myeloid neoplasms and (ii) discuss the reported risk of MDS/AML with PARPi, especially as the indications for PARPi use expand to include patients with potentially curable cancer.
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Mueller, Nancy, Stephen Luen, Roger Stupp, Anthony Chalmers, Baisong Huang, Massimo Squatrito, Barry Davies, Petra Hamerlik, and Timothy Yap. "CTNI-03. A PHASE I/IIA, OPEN-LABEL STUDY OF THE BRAIN-PENETRANT PARP1-SELECTIVE INHIBITOR AZD9574 AS MONOTHERAPY AND IN COMBINATION IN PATIENTS WITH ADVANCED SOLID MALIGNANCIES (CERTIS1)." Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii70. http://dx.doi.org/10.1093/neuonc/noac209.270.
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Abstract BACKGROUND Currently approved Poly ADP-Ribose Polymerase (PARP) inhibitors (PARPi) selectively inhibit and trap both PARP1 and PARP2 (PARP1/2) at sites of single strand (ss) deoxyribonucleic acid (DNA) (ssDNA) damage, preventing ssDNA repair and leading to replication-dependent DNA double strand breaks. Recent data suggest that only inhibition of PARP1 is required for anti-proliferative effects, while PARP2 functions in the survival of haematopoietic stem and progenitor cells. These observations suggest that the inhibition and trapping of PARP 2 is not needed for anti-cancer effects, and may be a major driver of haematological toxicity observed. AZD9574 is a novel brain-penetrant PARPi that potently and selectively inhibits and traps PARP1, with the goal of delivering efficacious, less toxic, and more combinable PARPi. Furthermore, owing to its central nervous system penetration capability, AZD9574 may provide a new treatment option for patients with CNS malignancies or patients with brain metastases characterized by homologous recombination deficiency (HRD). METHODS This is a first-in-human modular study primarily designed to evaluate the safety and tolerability of AZD9574 as monotherapy and in combination with anti-cancer agents at increasing dose levels in patients with advanced solid malignancies, followed by expansion cohorts in specific indications. The study will also characterize the pharmacokinetics of AZD9574 and explore potential biological activity by assessing pharmacodynamic and exploratory biomarkers and anti-tumour activity. Module 1 will enrol patients with advanced breast, ovarian, pancreatic or prostate tumours harbouring homologous recombination deficiencies. Module 2 will enrol patients with isocitrate dehydrogenase (IDH)1/2 mutated glioma.
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Krastev, Dragomir B., and Chris Lord. "Abstract 804: Trapped PARP1 cytotoxicity is modulated by the ubiquitin-dependentsegregase p97." Cancer Research 82, no. 12_Supplement (June 15, 2022): 804. http://dx.doi.org/10.1158/1538-7445.am2022-804.
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Abstract Poly-(ADP-ribose) polymerase inhibitors (PARPi) elicit anti-tumor activity in homologous recombination defective cancers by promoting cytotoxic, chromatin-bound, “trapped” PARP1. Here we have elucidated a pathway that process trapped PARP1. By exploiting wild-type or trapping-resistant PARP1 transgenes combined with either a rapid immunoprecipitation mass-spectrometry of endogenous proteins (RIME)-based approach or PARP1 Apex2-proximity labelling linked to mass-spectrometry, we generated proteomic profiles of trapped and non-trapped PARP1 complexes. These experiments demonstrated an increase in the SUMO1/2 modifications upon trapping, as well as an interaction with the ubiquitin-regulated p97 ATPase (aka VCP). Subsequent experiments demonstrated that upon trapping, PARP1 is SUMOylated by the SUMO-ligase PIAS4 and subsequently ubiquitinated by the SUMO-targeted E3-ubiquitin ligase, RNF4, events that promote p97 recruitment and p97 ATPase-mediated removal of trapped-PARP1 from chromatin. Consistently, small molecule p97 complex inhibitors, including a metabolite of the clinically-used drug disulfiram, CuET that acts as a p97 sequestration agent, prolong PARP1 trapping and thus enhance PARPi-induced cytotoxicity in homologous recombination defective tumor cells and patient-derived tumor organoids. Taken together, these results suggest that p97 ATPase plays a key role in the processing of trapped PARP1 from chromatin and the response of homologous recombination defective tumor cells to PARPi. Citation Format: Dragomir B. Krastev, Chris Lord. Trapped PARP1 cytotoxicity is modulated by the ubiquitin-dependentsegregase p97 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 804.
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Yang, Chunsong, Krzysztof Wierbilowicz, Natalia M. Dworak, Song Yi Bae, Sachi B. Tengse, Nicki Abianeh, Justin M. Drake, et al. "Abstract B072: Induction of PARP7 creates a vulnerability for growth inhibition by RBN2397 in prostate cancer cells." Cancer Research 83, no. 11_Supplement (June 2, 2023): B072. http://dx.doi.org/10.1158/1538-7445.prca2023-b072.
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Abstract The ADP-ribosyltransferase PARP7 modulates protein function by conjugating ADP-ribose to the side chains of acceptor amino acids. PARP7 has been shown to affect gene expression in prostate cancer cells and certain other cell types by mechanisms that include transcription factor ADP-ribosylation. Here, we use a recently developed catalytic inhibitor to PARP7, RBN2397 (NCT04053673), to study the effects of PARP7 inhibition in androgen receptor-positive (AR+) and androgen receptor-negative (AR-) prostate cancer cells. Ribon Therapeutics developed RBN2397 as a first-in-class mono-ADP-ribosyltransferase inhibitor, and showed that it blocks PARP7 negative regulation of TBK1 [1]. We find that RBN2397 has nanomolar potency for inhibiting androgen-induced ADP-ribosylation of the androgen receptor. RBN2397 inhibits the growth of prostate cancer cells in culture when cells are treated with ligands that activate the androgen receptor (PC3-AR, VCaP, CWR22Rv1), or the aryl hydrocarbon receptor (PC3, DU145, NCI-H660), and induce PARP7 expression. We show that the growth inhibitory effects of RBN2397 are distinct from its enhancement of interferon signaling recently shown to promote tumor immunogenicity in lung cancer models [1]. Chemical inhibitors to PARP1 exert effects on cells by blocking enzyme function, but also via cytotoxic effects attributed to stabilizing PARP1-chromatin interactions in a process termed trapping [2]. Drug-induced trapping of PARP1 can be detected biochemically by immunoblotting the detergent-resistant chromatin fraction. We found that RBN2397 treatment of AR+ and AR- prostate cancer cells induces biochemical trapping of PARP7 within the nucleus, which was also detected by confocal microscopy. Potential therapeutic benefits of RBN2397 are likely to depend on the level of PARP7 expression, given its induction is necessary for growth inhibitory effects of RBN2397 in cell culture. As a first step towards evaluating whether PARP7 levels in human prostate cancer may be actionable with RBN2397, we used computational methods to analyze PARP7 gene expression data from primary prostate tumors and metastatic AR+ and AR- prostate tumors. To assess PARP7 mRNA levels, we used data from the online resource recount3, which uniformly reprocesses publicly available RNA-seq datasets using a Monorail analysis pipeline. Using the level of PARP7 expression in VCaP cells that confers sensitivity to RBN2397 as a threshold, 50% of primary tumors, 41% of metastatic AR- and 11% of AR+ tumors are predicted to have PARP7 expression levels that are sufficient for a response to RBN2397. Because RBN2397 can inhibit the growth of castration-resistant and neuroendocrine prostate cancer cells, PARP7 may be an actionable target in advanced prostate cancer. 1. Gozgit, J.M., et al., PARP7 negatively regulates the Type I interferon response in cancer cells and its inhibition triggers antitumor immunity. Cancer Cell, 2021. 39(9): p. 1214-1226 e10 2. Murai, J., et al., Trapping of PARP1 and PARP2 by Clinical PARP Inhibitors. Cancer Res, 2012. 72(21): p. 5588-99. Citation Format: Chunsong Yang, Krzysztof Wierbilowicz, Natalia M. Dworak, Song Yi Bae, Sachi B. Tengse, Nicki Abianeh, Justin M. Drake, Tarek Abbas, Aakrosh Ratan, David Wotton, Bryce M. Paschal. Induction of PARP7 creates a vulnerability for growth inhibition by RBN2397 in prostate cancer cells [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B072.
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Kirby, Ilsa T., Ashley Person, and Michael Cohen. "Rational design of selective inhibitors of PARP4." RSC Medicinal Chemistry 12, no. 11 (2021): 1950–57. http://dx.doi.org/10.1039/d1md00195g.
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Mukherjee, Joydeep, Ajay Pandita, Chatla Kamalakar, Tor-Christian Johannessen, Shigeo Ohba, Yongjian Tang, Cecilia L. Dalle-Ore, Rolf Bjerkvig, and Russell O. Pieper. "A subset of PARP inhibitors induces lethal telomere fusion in ALT-dependent tumor cells." Science Translational Medicine 13, no. 592 (May 5, 2021): eabc7211. http://dx.doi.org/10.1126/scitranslmed.abc7211.
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About 10% of all tumors, including most lower-grade astrocytoma, rely on the alternative lengthening of telomere (ALT) mechanism to resolve telomeric shortening and avoid limitations on their growth. Here, we found that dependence on the ALT mechanism made cells hypersensitive to a subset of poly(ADP-ribose) polymerase inhibitors (PARPi). We found that this hypersensitivity was not associated with PARPi-created genomic DNA damage as in most PARPi-sensitive populations but rather with PARPi-induced telomere fusion. Mechanistically, we determined that PARP1 was recruited to the telomeres of ALT-dependent cells as part of a DNA damage response. By recruiting MRE11 and BRCC3 to stabilize TRF2 at the ends of telomeres, PARP1 blocked chromosomal fusion. Exposure of ALT-dependent tumor cells to a subset of PARPi induced a conformational change in PARP1 that limited binding to MRE11 and BRCC3 and delayed release of the TRF2-mediated block on lethal telomeric fusion. These results therefore provide a basis for PARPi treatment of ALT-dependent tumors, as well as establish chromosome fusion as a biomarker of their activity.
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Cowley, Phillip M., Barry E. McGuinness, Gillian M. Campbell, and Alan Wise. "Abstract 6172: Characterization of a novel series of highly selective PARP1 inhibitors." Cancer Research 83, no. 7_Supplement (April 4, 2023): 6172. http://dx.doi.org/10.1158/1538-7445.am2023-6172.
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Abstract First-generation PARP1 inhibitors have provided significant therapeutic benefit to patients whose tumors exhibit homologous repair deficiencies, including BRCA mutations, however their use has been associated with hematological toxicities that have restricted their application, particularly in combination with standard-of-care chemotherapy. All four FDA-approved PARP1 inhibitors are largely non-selective for the closely related enzyme PARP2, inhibition of which has been shown to drive hematotoxicity. Hence, the development of second-generation molecules highly selective for PARP1 over PARP2 offers a significant opportunity to 1) dramatically enhance therapeutic index, 2) enable additional precision medicine/combination approaches with chemotherapy, radiotherapy, immunotherapy and targeted agents and 3) expand the addressable patient population to those whose tumors harbor additional DDR defects. Utilizing X-ray crystallography and structure-based drug design, we describe the characterization of a novel chemical series of highly selective PARP1 inhibitors. These molecules demonstrate high potency in multiple biochemical and cell-based assays, including viability and colony forming unit read-outs in BRCA-deficient cancer cells, whilst sparing isogenically-paired BRCA wild-type cells and non-transformed primary cell lines. The molecules are potent PARP1-DNA trappers and exhibit high affinity, high selectivity and prolonged residence time in biophysical surface plasmon resonance (SPR) binding assays. The molecules also demonstrate exceptionally high selectivity for PARP1 over PARP2, and across the mono and polyPARP family, using a cell-based NanoBRET target engagement assay. This chemical series generally exhibits highly desirable physico-chemical and in vitro ADME properties, coupled with an excellent in vitro safety profile, which translate to high oral bioavailability and low clearance in rodent PK studies. Lead molecules yield deep and durable anti-tumor efficacy in a BRCA1m MDA-MB-436 breast cancer xenograft model with responses continuing after cessation of treatment. Percent tumor regression and post-dose tumor control was superior to olaparib at 1/10th of the dose. Importantly, our molecules demonstrate prolonged tumor residence time and a markedly superior tumor:plasma ratio compared to competitor PARP1-selective inhibitors. Taken together, these data predict low therapeutic dosing with the potential to demonstrate improved efficacy and tolerability compared to marketed PARP inhibitors. In summary, we describe the characterization of novel potent and selective PARP1 inhibitors. These molecules demonstrate excellent in vitro ADMET and in vivo PK, coupled with profound anti-tumor efficacy and tumor-targeting properties in a genetically-defined mouse model, supporting their progression into clinical studies. Citation Format: Phillip M. Cowley, Barry E. McGuinness, Gillian M. Campbell, Alan Wise. Characterization of a novel series of highly selective PARP1 inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6172.
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Pommier, Y., S. H. Huang, B. B. Das, A. Renaud, Y. Zhang, S. H. Takeda, and J. H. Doroshow. "284 Differential Trapping of PARP1 and PARP2 by Clinical PARP Inhibitors." European Journal of Cancer 48 (November 2012): 87. http://dx.doi.org/10.1016/s0959-8049(12)72082-8.
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Malyuchenko, N. V., E. Yu Kotova, O. I. Kulaeva, M. P. Kirpichnikov, and V. M. Studitskiy. "PARP1 Inhibitors: Antitumor Drug Design." Acta Naturae 7, no. 3 (September 15, 2015): 27–37. http://dx.doi.org/10.32607/20758251-2015-7-3-27-37.
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The poly (ADP-ribose) polymerase 1 (PARP1) enzyme is one of the promising molecular targets for the discovery of antitumor drugs. PARP1 is a common nuclear protein (1-2 million molecules per cell) serving as a sensor for DNA strand breaks. Increased PARP1 expression is sometimes observed in melanomas, breast cancer, lung cancer, and other neoplastic diseases. The PARP1 expression level is a prognostic indicator and is associated with a poor survival prognosis. There is evidence that high PARP1 expression and treatment-resistance of tumors are correlated. PARP1 inhibitors are promising antitumor agents, since they act as chemo- and radiosensitizers in the conventional therapy of malignant tumors. Furthermore, PARP1 inhibitors can be used as independent, effective drugs against tumors with broken DNA repair mechanisms. Currently, third-generation PARP1 inhibitors are being developed, many of which are undergoing Phase II clinical trials. In this review, we focus on the properties and features of the PARP1 inhibitors identified in preclinical and clinical trials. We also describe some problems associated with the application of PARP1 inhibitors. The possibility of developing new PARP1 inhibitors aimed at DNA binding and transcriptional activity rather than the catalytic domain of the protein is discussed.
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Krastev, Dragomir B., Shudong Li, Yilun Sun, Andrew J. Wicks, Gwendoline Hoslett, Daniel Weekes, Luned M. Badder, et al. "The ubiquitin-dependent ATPase p97 removes cytotoxic trapped PARP1 from chromatin." Nature Cell Biology 24, no. 1 (January 2022): 62–73. http://dx.doi.org/10.1038/s41556-021-00807-6.
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AbstractPoly (ADP-ribose) polymerase (PARP) inhibitors elicit antitumour activity in homologous recombination-defective cancers by trapping PARP1 in a chromatin-bound state. How cells process trapped PARP1 remains unclear. Using wild-type and a trapping-deficient PARP1 mutant combined with rapid immunoprecipitation mass spectrometry of endogenous proteins and Apex2 proximity labelling, we delineated mass spectrometry-based interactomes of trapped and non-trapped PARP1. These analyses identified an interaction between trapped PARP1 and the ubiquitin-regulated p97 ATPase/segregase. We found that following trapping, PARP1 is SUMOylated by PIAS4 and subsequently ubiquitylated by the SUMO-targeted E3 ubiquitin ligase RNF4, events that promote recruitment of p97 and removal of trapped PARP1 from chromatin. Small-molecule p97-complex inhibitors, including a metabolite of the clinically used drug disulfiram (CuET), prolonged PARP1 trapping and enhanced PARP inhibitor-induced cytotoxicity in homologous recombination-defective tumour cells and patient-derived tumour organoids. Together, these results suggest that p97 ATPase plays a key role in the processing of trapped PARP1 and the response of tumour cells to PARP inhibitors.
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Ganguly, Bratati, Sonia C. Dolfi, Lorna Rodriguez-Rodriguez, Shridar Ganesan, and Kim M. Hirshfield. "Role of Biomarkers in the Development of PARP Inhibitors." Biomarkers in Cancer 8s1 (January 2016): BIC.S36679. http://dx.doi.org/10.4137/bic.s36679.
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Defects in DNA repair lead to genomic instability and play a critical role in cancer development. Understanding the process by which DNA damage repair is altered or bypassed in cancer may identify novel therapeutic targets and lead to improved patient outcomes. Poly(adenosine diphosphateribose) polymerase 1 (PARP1) has an important role in DNA repair, and novel therapeutics targeting PARP1 have been developed to treat cancers with defective DNA repair pathways. Despite treatment successes with PARP inhibitors (PARPi), intrinsic and acquired resistances have been observed. Preclinical studies and clinical trials in cancer suggest that combination therapy using PARPi and platinating agents is more effective than monotherapy in circumventing drug resistance mechanisms. Additionally, identification of biomarkers in response to PARPi will lead to improved patient selection for targeted cancer treatment. Recent technological advances have provided the necessary tools to examine many potential avenues to develop such biomarkers. This review examines the mechanistic rationale of PARP inhibition and potential biomarkers in their development for personalized therapy.
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Maifrede, Silvia, Margaret Nieborowska-Skorska, Katherine Sullivan-Reed, Yashodhara Dasgupta, Paulina Podszywalow-Bartnicka, Bac Viet Le, Martyna Solecka, et al. "Tyrosine kinase inhibitor–induced defects in DNA repair sensitize FLT3(ITD)-positive leukemia cells to PARP1 inhibitors." Blood 132, no. 1 (July 5, 2018): 67–77. http://dx.doi.org/10.1182/blood-2018-02-834895.
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Key Points FLT3 inhibitor AC220 caused DNA repair defects and sensitized FLT3(ITD)-positive AML stem and progenitor cells to PARP1 inhibitors. Quiescent and proliferating FLT3(ITD)-positive AML cells were eliminated by the combination of FLT3 and PARP1 inhibitors.
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Nguyen, Dang Hai, Zhiyan Silvia Liu, Sayantani Sinha, Maxwell Bannister, Erica Arriaga-Gomez, Axia Song, Dawei Zong, et al. "Spliceosome Mutant Myeloid Malignancies Are Preferentially Sensitive to PARP Inhibition." Blood 138, Supplement 1 (November 5, 2021): 322. http://dx.doi.org/10.1182/blood-2021-149688.
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Abstract Somatic heterozygous mutations in spliceosome genes SRSF2, U2AF1, and SF3B1 commonly occur in patients with myeloid malignancies such as myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Moreover, SRSF2 and U2AF1 mutations associate with poor survival and high risk of progression to AML, representing a unique genetic vulnerability for targeted therapy. We and others previously found that R-loops, a group of transcription intermediates containing RNA:DNA hybrids and displaced single-stranded DNA, are a source of genomic instability induced by different spliceosome mutants. We further showed that inhibition of ATR kinase activity preferentially kills spliceosome mutant cells in an R-loop-dependent manner. Inspired by ATR inhibition results, we performed a focused drug screen with inhibitors targeting additional DNA damage response pathways to identify novel therapeutic vulnerabilities generated by spliceosome mutations. We generated a murine leukemia model by overexpressing the MLL-AF9 fusion oncogene on an Srsf2 P95H/+background, a mutational combination that is found in ~10% of MLL-rearranged leukemias. Surprisingly, we found that Srsf2 P95H/+cells are more sensitive to five inhibitors targeting ADP-ribosyltransferases or PARP (olaparib, talazoparib, rucaparib, niraparib, veliparib) (Figs 1A-B). Olaparib (PARPi)-treated Srsf2 P95H/+cells exhibited increased apoptosis compared to Srsf2 +/+ cells as determined by AnnexinV (Fig 1C). PARPi sensitivity was also observed in isogenic murine MLL-AF9 U2af1 S34F/+cells compared to MLL-AF9 U2af1 +/+ cells (Fig 1D). These data highlight that both SRSF2 P95H and U2AF1 S34F mutations create a common vulnerability that is dependent on PARP activity for survival. To evaluate PARP activity in cells, we used isogenic K562 leukemia cells expressing SRSF2 P95H and U2AF1 S34F mutations from their endogenous loci and monitored PAR (poly(ADP-ribose)) chain levels, a marker of PARP activity. Both SRSF2 P95H and U2AF1 S34F cells exhibited elevated PAR levels compared to wildtype cells (Figs 1E-F). PARPi treatment significantly suppressed PAR signals in SRSF2 P95H and U2AF1 S34F cells. PARP inhibitors target both PARP1 and PARP2 enzymes, of which PARP1 plays a key role in DNA damage response. We used CRISPR-Cas9 to knockout PARP1 gene to determine the major PARP responsible for elevated PAR level in these leukemia cells. PARP1 deletion abrogated elevated PAR levels in U2AF1 S34F (Fig 1G) and SRSF2 P95H cells (data not shown). Altogether, we demonstrated that SRSF2 P95H and U2AF1 S34F cells trigger a PARP1 response critical for cell survival. To test whether increased PAR level arises from U2AF1 S34F-induced R-loops, we generated U2AF1 S34F cells that inducibly express RNaseH1, an enzyme that specifically cleaves the RNA moiety within RNA:DNA hybrids. Induction of RNaseH1 in U2AF1 S34F cells significantly reduced PAR levels, showing that U2AF1 S34F-induced PAR chains is R-loop-dependent (Fig 1H). Moreover, RNaseH1 overexpression suppressed the growth inhibition of PARPi-treated U2AF1 S34F cells (Fig 1I). Collectively, these results suggest that U2AF1 S34F mutants induce R-loop accumulation and elicit an R-loop-associated PARP1 signaling to promote cell survival. We next tested whether combining ATR inhibitor (ATRi) can further exacerbate PARPi sensitivity in spliceosome mutant cells. To examine ATR activity, we monitored phosphorylated RPA (Replication Protein A, or pRPA), a known ATR substrate. pRPA level was enhanced in PARPi-treated SRSF2 P95H cells compared to PARPi-treated SRSF2 WT cells but was suppressed when treated with ATRi (Fig 1J), suggesting that splicing factor mutant cells are more reliant on ATR function in the context of PARPi. Importantly, the combination of PARPi with ATRi, but not with ATMi, significantly promoted cell growth inhibition in SRSF2 P95H cells compared to SRSF2 WT cells or to SRSF2 P95H cells treated with individual compounds alone (Fig 1K). Collectively, these data provide a pre-clinical rationale that splicing factor mutant leukemias are preferentially sensitive to PARP1 modulation compared to their wildtype counterpart. Moreover, combining PARPi and ATRi may further sensitize spliceosome mutant cells and could represent a new therapeutic strategy in myeloid leukemia patients harboring these mutations (Fig 1L). Figure 1 Figure 1. Disclosures Graubert: Calico: Research Funding; Janssen: Research Funding; astrazeneca: Research Funding.
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Caracciolo, Daniele, Francesca Scionti, Giada Juli, Emanuela Altomare, Gaetanina Golino, Katia Todoerti, Katia Grillone, et al. "Exploiting MYC-induced PARPness to target genomic instability in multiple myeloma." Haematologica 106, no. 1 (February 20, 2020): 185–95. http://dx.doi.org/10.3324/haematol.2019.240713.
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Multiple Myeloma (MM) is a hematologic malignancy strongly characterized by genomic instability, which promotes disease progression and drug resistance. Since we previously demonstrated that LIG3-dependent repair is involved in the genomic instability, drug resistance and survival of MM cells, we here investigated the biological relevance of PARP1, a driver component of Alternative-Non Homologous End Joining (Alt-NHEJ) pathway, in MM. We found a significant correlation between higher PARP1 mRNA expression and poor prognosis of MM patients. PARP1 knockdown or its pharmacological inhibition by Olaparib impaired MM cells viability in vitro and was effective against in vivo xenografts of human MM. Anti-proliferative effects induced by PARP1-inhibition were correlated to increase of DNA double-strand breaks, activation of DNA Damage Response (DDR) and finally apoptosis. Importantly, by comparing a gene expression signature of PARP inhibitors (PARPi) sensitivity to our plasma cell dyscrasia (PC) gene expression profiling (GEP), we identified a subset of MM patients which could benefit from PARP inhibitors. In particular, Gene Set Enrichment Analysis (GSEA) suggested that high MYC expression correlates to PARPi sensitivity in MM. Indeed, we identified MYC as promoter of PARP1-mediated repair in MM and, consistently, we demonstrate that cytotoxic effects induced by PARP inhibition are mostly detectable on MYC-proficient MM cells. Taken together, our findings indicate that MYC-driven MM cells are addicted to PARP1 Alt-NHEJ repair, which represents therefore a druggable target in this still incurable disease.
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Shen, Xiaokun, and Zeng Li. "Abstract P5-05-09: Cvl218,a second-generation selective parp inhibitors with strong clinical potential for breast cancer." Cancer Research 82, no. 4_Supplement (February 15, 2022): P5–05–09—P5–05–09. http://dx.doi.org/10.1158/1538-7445.sabcs21-p5-05-09.
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Abstract CVL218 is a second-generation, potent and selective PARP1/2 inhibitor and now underinvestigated at Ib/II clinical stage in China. Pharmacokinetic studies in rats showed thatCVL218 show best in class tissue distribution profiles and can across the blood-brain barrier (BBB) because of its optimally balanced water-liposolubility, indicating its therapeutic potential in various solid tumors including brain and/or brain metastasis tumor. Besides the superior DMPK properties, CVL218 perform best in class safety dataover the first-generation PARPi in Ia clinical stage which indicates a wider combination usage with other promising therapies such as checkpoint inhibitors and chemotherapies. Here, we report the in vitro and in vivo preclinic outcomes of CVL218 combination usage. These findings suggest that CVL218 is a potential agent for both mono- and combination treatment on various solid tumors including breast cancer.Results:1. PARP enzymes activity, selectivity and solubility CVL218 have a strong potency and better selectivity on PARP1/2 over PARP3/5/6compared with the first-generation PARPi Olaparib and second-generation AZD5305. Furthermore, the Solubility of CVL218 is far more superior than other PARPis. (Table 1) 2. in vitro efficacy of CVL218 combination on breast cancer cell lines In vitro cell-based studies implied that CVL218 could sensitizing the cell proliferation. inhibition of chemotherapies including Taxol and Temozolomide (TMZ) on HRDnegative solid tumors such as breast cancer cell lines, indication the potential for combination use (Table 2). Since TMZ is the first-line drug for treating glioma, CVL218 is also expected for positive outcomes in further clinical trials.(Table 2) 3. Xenograft study of CVL218 combi with checkpoint inhibitorCVL218 was tested alone with PD-1 inhibitor geptanolimab on MDA-MB-436 breast cancer CDX model (NCG, PMBC Humanized, N=10). Formonotherapy, CVL218 (40mpk) was more potent than geptanolimab (10 mpk). WhenCVL218 in combination with geptanolimab, significate tumor growth inhibition was presented compared with PD-1 monotherapy (p<0.01). Moreover, CVL218 possessed very promising safety profiles in both monotherapy and combination therapy. Among all groups, no animal was dead for drug toxicity. The results indicate a very promising prospect for the use of CVL218 combi with checkpoint inhibitor. Conclusions:. CVL218 is a second-generation PARP1/2 inhibitor with strong potency, selectivity,outstanding drug-like properties and very promising safety profiles. In vivo data reveal optimistic expectations for the clinical development of combination usage of CVL218 with chemotherapy and checkpoint inhibitor on solid tumors such as breast cancer. Now Ib/IIclinic trials of CVL218 on solid tumors is conducted in China and combination therapy with chemotherapy and checkpoint inhibitor are expected to start in later 2021. Table 1.PARP enzymes activity, selectivity and solubilityPARPsCVL218CVL218OlaparibOlaparibAZD5305AZD5305IC50 (nM)FoldIC50 (nM)FoldIC50 (nM)FoldPARP13.21.001.11.003.01.00PARP21.90.590.90.82>1.4>466PARP3>10000>3125258234.5534001133TNKS11600500.0014.5–>89000>29666TNKS21300406.255.9–––PARP6>10000>312515001363.64260008666Solubility35 mg/mL<0.01 mg/mL~ 0.02 mg/mL Citation Format: Xiaokun Shen, Zeng Li. Cvl218,a second-generation selective parp inhibitors with strong clinical potential for breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-05-09.
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Li, Dongyue. "The Recent Advances of PARP Inhibitors in the Treatment of Cancer." Theoretical and Natural Science 3, no. 1 (April 28, 2023): 855–61. http://dx.doi.org/10.54254/2753-8818/3/20220498.
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This article introduces the discovery and research progress of Poly-ADP-ribose polymerases (PARP) inhibitors. The catalytic sites of PARP1 and PARP2 are designed as competitive inhibitors of NAD+, so that DNA single-strand repair cannot be completed through the combination of PARP1 and NAD+.PARP is quite crucial in the process of DNA single-strand damage repair. Inhibiting PARP function will interfere with normal DNA repair and induce DNA damage accumulation into more serious double-strand breaks through replication fork folding. Homologous recombination (HR) repair is the main way of double DNA repair, which needs to be mediated by key proteins BRCA1 and BRCA2. In the same way, blocking the single chain repair and HR pathway, the synergistic lethal effect produced by combining these two nonlethal mechanisms, namely the synthetic lethality mechanism, provides a theoretical basis for PARPi. Olaparib was approved for clinical by FDA for the first time through this mechanism. The efficacy of Olaparib in the four approved indications was confirmed in clinical trials. It can benefit patients by improving the progress-free survival or objective response rate, and its safety is better than chemotherapy drugs. Even more clinically valuable combination of platinum and chemotherapy drugs has been proven to benefit significantly. At last, the paper pointed out the development emphasis and prospect of PARP inhibitors in the future.
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Ambur Sankaranarayanan, Ramya, Susanne Kossatz, Wolfgang Weber, Mohsen Beheshti, Agnieszka Morgenroth, and Felix M. Mottaghy. "Advancements in PARP1 Targeted Nuclear Imaging and Theranostic Probes." Journal of Clinical Medicine 9, no. 7 (July 6, 2020): 2130. http://dx.doi.org/10.3390/jcm9072130.
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The central paradigm of novel therapeutic approaches in cancer therapy is identifying and targeting molecular biomarkers. One such target is the nuclear DNA repair enzyme Poly-(ADP ribose) polymerase 1 (PARP1). Sensitivity to PARP inhibition in certain cancers such as gBRCAmut breast and ovarian cancers has led to its exploitation as a target. The overexpression of PARP1 in several types of cancer further evoked interest in its use as an imaging target. While PARP1-targeted inhibitors have fast developed and approved in this past decade, determination of PARP1 expression might help to predict the response to PARP inhibitor treatment. This has the potential of improving prognosis and moving towards tailored therapy options and/or dosages. This review summarizes the recent pre-clinical advancements in imaging and theranostic PARP1 targeted tracers. To assess PARP1 levels, several imaging probes with fluorescent or beta/gamma emitting radionuclides have been proposed and three have advanced to ongoing clinical evaluation. Apart from its diagnostic value in detection of primary tumors as well as metastases, this shall also help in delivering therapeutic radionuclides to PARP1 overexpressing tumors. Henceforth nuclear medicine has now advanced towards conjugating theranostic radionuclides to PARP1 inhibitors. This paves the way for a future of PARP1-targeted theranostics and personalized therapy.
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Ge, Jun, Yu Yin, Yingpeng Li, Yanru Deng, and Hui Fu. "Dual-target inhibitors based on PARP1: new trend in the development of anticancer research." Future Medicinal Chemistry 14, no. 7 (April 2022): 511–25. http://dx.doi.org/10.4155/fmc-2021-0292.
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PARP1 is a hot target, and its inhibitors have been approved for cancer therapy. However, some undesirable properties restrict the application of PARP1 inhibitors, including drug resistance, side effects and low efficiency. For multifactorial diseases, dual-target drugs have exhibited excellent synergistic effects, such as reduced drug resistance, low side effects and high therapeutic efficacy, by simultaneously regulating the main pathogenic and compensatory signal pathways of diseases. In recent years, several dual-target inhibitors based on PARP1 have been reported and have demonstrated unique advantages. In this review we summarize the research progress in dual-target inhibitors based on PARP1 and discuss the related drug design strategies and structure–activity relationships. This work is expected to provide references for the development of PARP1 inhibitors.
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Conceição, Carlota J. F., Elin Moe, Paulo A. Ribeiro, and Maria Raposo. "Liposome Formulations for the Strategic Delivery of PARP1 Inhibitors: Development and Optimization." Nanomaterials 13, no. 10 (May 11, 2023): 1613. http://dx.doi.org/10.3390/nano13101613.
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The development of a lipid nano-delivery system was attempted for three specific poly (ADP-ribose) polymerase 1 (PARP1) inhibitors: Veliparib, Rucaparib, and Niraparib. Simple lipid and dual lipid formulations with 1,2-dipalmitoyl-sn-glycero-3-phospho-rac-(1′-glycerol) sodium salt (DPPG) and 1,2-dipalmitoyl-sn-glycero-3-phosphocoline (DPPC) were developed and tested following the thin-film method. DPPG-encapsulating inhibitors presented the best fit in terms of encapsulation efficiency (>40%, translates into concentrations as high as 100 µM), zeta potential values (below −30 mV), and population distribution (single population profile). The particle size of the main population of interest was ~130 nm in diameter. Kinetic release studies showed that DPPG-encapsulating PARP1 inhibitors present slower drug release rates than liposome control samples, and complex drug release mechanisms were identified. DPPG + Veliparib/Niraparib presented a combination of diffusion-controlled and non-Fickian diffusion, while anomalous and super case II transport was verified for DPPG + Rucaparib. Spectroscopic analysis revealed that PARP1 inhibitors interact with the DPPG lipid membrane, promoting membrane water displacement from hydration centers. A preferential membrane interaction with lipid carbonyl groups was observed through hydrogen bonding, where the inhibitors’ protonated amine groups may be the major players in the PARP1 inhibitor encapsulation mode.
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Nguyen, Dang Hai, Sayantani Sinha, Zhiyan Silvia Liu, Maxwell Henry Bannister, Erica Arriaga-Gomez, Axia Song, Dawei Zong, et al. "Abstract 6183: PARP inhibitors preferentially sensitize splicing factor mutant myeloid neoplasms." Cancer Research 83, no. 7_Supplement (April 4, 2023): 6183. http://dx.doi.org/10.1158/1538-7445.am2023-6183.
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Abstract Somatic heterozygous mutations in genes encoding for RNA splicing factors (SF) SRSF2, U2AF1, and SF3B1 are frequently mutated in patients with hematologic malignancies, representing a unique genetic vulnerability for targeted therapy. In the current study, we performed a focused drug screen with inhibitors targeting different DNA damage response and DNA metabolic pathways to identify novel therapeutic vulnerabilities generated by SF mutations. We generated a murine leukemia model by overexpressing the MLL-AF9 fusion oncogene on an Srsf2P95H/+ background, a mutational combination that is found in ~10% of MLL-rearranged leukemias. We surprisingly found that MLL-AF9 Srsf2P95H/+ mutant leukemias are sensitive to inhibitors targeting ADP-ribosyltransferases (PARP). PARP inhibitor sensitivity was also observed in isogenic murine MLL-AF9 U2af1s34/+ cells compared to MLL-AF9 U2af1+/+ cells. Second, murine Srsf2P95H leukemias showed improved prolonged survival when treated with olaparib (PARPi) compared to vehicle treatment in vivo. Third, human primary AML patient samples that harbor SF mutations are sensitive to PARPi compared to non-SF mutant samples. These data highlight that both SRSF2P95H and U2AF1S34F mutations create a common vulnerability that is dependent on PARP activity for survival. To evaluate PARP activity, we used isogenic K562 leukemia cells expressing SRSF2P95H and U2AF1S34F mutations from their endogenous loci and monitored ADP-ribosylation (ADPr) levels, a marker of PARP activity. Both SRSF2P95H and U2AF1S34F cells exhibited elevated levels of ADPr compared to wildtype cells in a PARP1- dependent manner. PARPi preferentially induced DNA damage and cell death in SF mutant cells. Surprisingly, we found that SRSF2P95H and U2AF1S34F cells are not defective in homologous recombination repair. Instead, the increased PARP1-mediated ADPr in SF-mutant cells is caused by accumulated R loops, a group of transcription intermediates containing RNA:DNA hybrids and displaced single-stranded DNA. To determine whether PARPi sensitivity is due to R-loop accumulation, we overexpressed RNase H1, an enzyme that specifically cleaves the RNA moiety within RNA:DNA hybrids in U2AF1S34F cells. Overexpression of RNase H1 significantly reduced ADPr levels and suppressed the PARPi-induced U2AF1S34F cell growth inhibition. Collectively, these results suggest that spliceosome mutants induce R-loop accumulation and elicit an R-loop-associated PARP1 response to promote cell survival. In summary, our data establish a previously unknown link between R-loop-induced PARP1 response and RNA splicing perturbation and provide a mechanistic rationale to evaluate the clinical efficacy of PARP inhibitors in spliceosome-mutant malignancies. Furthermore, our study highlights a new therapeutic potential of targeting the R-loop tolerance pathways caused by different spliceosome gene mutations. Citation Format: Dang Hai Nguyen, Sayantani Sinha, Zhiyan Silvia Liu, Maxwell Henry Bannister, Erica Arriaga-Gomez, Axia Song, Dawei Zong, Martina Sarchi, Victor Corral, Wannasiri Chiraphapphaiboon, Jennifer Yoo, Matthew McMahon, Cassandra Leibson, Derek L. Stirewalt, H Joachim Deeg, Sumit Rai, Matthew Walter, Timothy A. Graubert, Sergei Doulatov, Stanley C. Lee. PARP inhibitors preferentially sensitize splicing factor mutant myeloid neoplasms. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6183.
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Juhász, Szilvia, Rebecca Smith, Tamás Schauer, Dóra Spekhardt, Hasan Mamar, Siham Zentout, Catherine Chapuis, Sébastien Huet, and Gyula Timinszky. "The chromatin remodeler ALC1 underlies resistance to PARP inhibitor treatment." Science Advances 6, no. 51 (December 2020): eabb8626. http://dx.doi.org/10.1126/sciadv.abb8626.
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Poly(ADP-ribose) polymerase (PARP) inhibitors are used in the treatment of BRCA-deficient cancers, with treatments currently extending toward other homologous recombination defective tumors. In a genome-wide CRISPR knockout screen with olaparib, we identify ALC1 (Amplified in Liver Cancer 1)—a cancer-relevant poly(ADP-ribose)-regulated chromatin remodeling enzyme—as a key modulator of sensitivity to PARP inhibitor. We found that ALC1 can remove inactive PARP1 indirectly through binding to PARylated chromatin. Consequently, ALC1 deficiency enhances trapping of inhibited PARP1, which then impairs the binding of both nonhomologous end-joining and homologous recombination repair factors to DNA lesions. We also establish that ALC1 overexpression, a common feature in multiple tumor types, reduces the sensitivity of BRCA-deficient cells to PARP inhibitors. Together, we conclude that ALC1-dependent PARP1 mobilization is a key step underlying PARP inhibitor resistance.
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Truong, Sarah, Louise Ramos, Beibei Zhai, Jay Joshi, Fariba Ghaidi, Michael M. Lizardo, Taras Shyp, et al. "Abstract 6194: A bifunctional inhibitor of PARP and HDAC enzymes with activity in Ewing sarcoma 3D spheroid and metastasis models." Cancer Research 83, no. 7_Supplement (April 4, 2023): 6194. http://dx.doi.org/10.1158/1538-7445.am2023-6194.
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Abstract Introduction: Poly(ADP-ribose) polymerase (PARP) plays a major role in DNA repair and PARP inhibitors (PARPi) have shown promise in pre-clinical studies for the treatment of Ewing sarcoma (ES). While a clinical trial using olaparib as a single agent failed to show significant response against ES, combination therapies with PARPi have emerged as an area of interest. Deacetylation of histones, controlled by histone deacetylases (HDACs) is a key regulatory event in DNA repair and inhibition of HDACs has been shown to reduce ES tumor growth in vitro and in vivo. PARP inhibition combined with HDAC inhibition has demonstrated enhanced efficacy in pre-clinical studies in various tumor indications, and a clinical trial of olaparib and vorinostat combination therapy against metastatic breast cancer is currently ongoing. However, combination therapies can be limited in clinical utility due to overlapping toxicities and different pharmacokinetic profiles. Here, we report the efficacy of a novel bifunctional small-molecule compound, kt-3283, designed to have both PARP and HDAC inhibitory activities. Materials and methods: PARP1 and PARP2 activity were measured using Trevigen Universal Colorimetric PARP Assay Kit, BPS Bioscience PARP2 Colorimetric PARP2 Assay Kit, and PARylation assay. HDAC activity was measured using HeLa cell nuclear extracts and a fluorogenic peptide-based biochemical assay. Cell survival EC50s were determined using live cell imaging with an Incucyte® S3 system and CellTiter Glo viability assay. Cell cycle analysis was performed by flow cytometry with propidium iodide staining. DNA damage was investigated by western blot, immunofluorescence, and comet assay. Spheroid assays were performed using the Incucyte® S3 spheroid analysis module and inhibition of metastases was assessed in a PUMA ES mouse model. Results and discussion: Kt-3283 showed potent inhibition of PARP1/2 activity and PAR synthesis with IC50 values comparable to olaparib. Kt-3283 also showed inhibition of HDACs with an IC50 value in the low µM range. Cell survival EC50 values for the compound were also superior to those of olaparib and vorinostat in ES cell lines. Cell cycle and DNA damage analyses indicated S/G2/M cell cycle arrest and strong DNA damage upon treatment with kt-3283 at lower concentration range compared to olaparib and vorinostat. This compound also exhibited potent inhibition of 3D spheroid growth of ES cells with low µM EC50 values, and inhibited metastatic growth in a PUMA mouse model. Conclusion: Kt-3283 shows potent inhibition of PARP1/2 and HDAC activities. It induces S and G2/M cell cycle arrest and DNA damage, and inhibits 3D spheroid growth and metastatic potential of ES cells. Further investigation of this bifunctional single-molecule inhibitor may offer a novel treatment opportunity for ES and other solid tumors with limited responses to PARPi. Citation Format: Sarah Truong, Louise Ramos, Beibei Zhai, Jay Joshi, Fariba Ghaidi, Michael M. Lizardo, Taras Shyp, John Langlands, Dennis Brown, Jeffrey Bacha, Poul Sorensen, Wang Shen, Mads Daugaard. A bifunctional inhibitor of PARP and HDAC enzymes with activity in Ewing sarcoma 3D spheroid and metastasis models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6194.
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Demény, Máté A., and László Virág. "The PARP Enzyme Family and the Hallmarks of Cancer Part 2: Hallmarks Related to Cancer Host Interactions." Cancers 13, no. 9 (April 24, 2021): 2057. http://dx.doi.org/10.3390/cancers13092057.
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Poly (ADP-ribose) polymerases (PARPs) modify target proteins with a single ADP-ribose unit or with a poly (ADP-ribose) (PAR) polymer. PARP inhibitors (PARPis) recently became clinically available for the treatment of BRCA1/2 deficient tumors via the synthetic lethality paradigm. This personalized treatment primarily targets DNA damage-responsive PARPs (PARP1–3). However, the biological roles of PARP family member enzymes are broad; therefore, the effects of PARPis should be viewed in a much wider context, which includes complex effects on all known hallmarks of cancer. In the companion paper (part 1) to this review, we presented the fundamental roles of PARPs in intrinsic cancer cell hallmarks, such as uncontrolled proliferation, evasion of growth suppressors, cell death resistance, genome instability, replicative immortality, and reprogrammed metabolism. In the second part of this review, we present evidence linking PARPs to cancer-associated inflammation, anti-cancer immune response, invasion, and metastasis. A comprehensive overview of the roles of PARPs can facilitate the identification of novel cancer treatment opportunities and barriers limiting the efficacy of PARPi compounds.
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Dallavalle, Sabrina, Salvatore Princiotto, Luce M. Mattio, Roberto Artali, Loana Musso, Anna Aviñó, Ramon Eritja, Claudio Pisano, Raimundo Gargallo, and Stefania Mazzini. "Investigation of the Complexes Formed between PARP1 Inhibitors and PARP1 G-Quadruplex at the Gene Promoter Region." International Journal of Molecular Sciences 22, no. 16 (August 14, 2021): 8737. http://dx.doi.org/10.3390/ijms22168737.
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DNA repair inhibitors are one of the latest additions to cancer chemotherapy. In general, chemotherapy produces DNA damage but tumoral cells may become resistant if enzymes involved in DNA repair are overexpressed and are able to reverse DNA damage. One of the most successful drugs based on modulating DNA repair are the poly(ADP-ribose) polymerase 1 (PARP1) inhibitors. Several PARP1 inhibitors have been recently developed and approved for clinical treatments. We envisaged that PARP inhibition could be potentiated by simultaneously modulating the expression of PARP 1 and the enzyme activity, by a two-pronged strategy. A noncanonical G-quadruplex-forming sequence within the PARP1 promoter has been recently identified. In this study, we explored the potential binding of clinically approved PARP1 inhibitors to the G-quadruplex structure found at the gene promoter region. The results obtained by NMR, CD, and fluorescence titration confirmed by molecular modeling demonstrated that two out the four PARP1 inhibitors studied are capable of forming defined complexes with the PARP1 G-quadruplex. These results open the possibility of exploring the development of better G-quadruplex binders that, in turn, may also inhibit the enzyme.
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Wang, Luyao, Chao Liang, Fangfei Li, Daogang Guan, Xiaoqiu Wu, Xuekun Fu, Aiping Lu, and Ge Zhang. "PARP1 in Carcinomas and PARP1 Inhibitors as Antineoplastic Drugs." International Journal of Molecular Sciences 18, no. 10 (October 8, 2017): 2111. http://dx.doi.org/10.3390/ijms18102111.
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Hiroki, Haruka, Masatoshi Takagi, Yuko Ishi, Jinhua Piao, and Tomohiro Morio. "PARP Inhibition Sensitize BCR-ABL1 Positive Cel." Blood 134, Supplement_1 (November 13, 2019): 3367. http://dx.doi.org/10.1182/blood-2019-127853.
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Introduction: BCR-ABL1 play a key role in the development of chronic myelogenous leukemia and a part of Ph1 positive acute lymphoblastic leukemia (ALL). BCR-ABL1 functions as a tyrosine kinase. Whereas, BCR-ABL1 induces genomic instability by downregulation of BRCA1. An innate error of BRCA1, a molecule involved in the homologous recombination repair pathway, causes hereditary breast and ovarian cancer. PARP inhibitor (PARPi) induces synthetic lethality in BRCA defective cell. Therefore, PARP inhibitor is expected to induce efficient cell death with BCR-ABL1 positive cell. In addition, in some previous reports, reduction of PARP1 activity leads to the upregulation of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway and BCR-ABL1 tyrosine kinase activates PI3K/AKT pathway. These findings suggest activation of the PI3K/AKT pathway leading to PARPi resistance in BCR-ABL1 positive leukemic cells. Here, we demonstrate that PARP inhibition attenuates BCR-ABL1 mediated leukemogenesis and aberration of factors associated with PARP inhibitor resistance induces cell death to fully transformed leukemic cells. Method: Bone marrow-derived mononuclear cells (MNC) from wild type mice and BCR-ABL1 transgenic (Tg) mice were exposed to PARPi in vivo, and cell death was analyzed Annexin-V positivity. PARPi sensitivity to BCR-ABL1 expressed cell was also investigated in vivo bone marrow transplantation model using mouse hematopoietic stem cell (HCS) infected with BCR-ABL1 expressing retrovirus. To evaluate more precisely the results obtained in vitro and in vivo transplantation model, the genetical approach was also performed. The Parp1 knockout (KO) mice were crossed with BCR-ABL1 Tg mice. Then, Leukemia development and subsequent mouse death were observed. In vitro, HR activity was examined using DR-GFP assay. Genomic instability was investigated using the breakage-fusion-bridge (BFB) generation.Maintenance of HSC as a progenitor of the leukemic cell was analyzed by repopulation activity using colony assay. The growth-inhibitory effect was assessed using BCR-ABL positive cell lines with PARPi and PI3K inhibitor. Results: BCR-ABL1 Tg mice derived MNC showed more hypersensitivity to PARPi. Mouse HCS was infected with BCR-ABL1 expressing retrovirus and transplanted lethally Olaparib or vehicle was administrated intraperitoneal injection one day after transplantation. BCR-ABL1 mediated leukemic death was observed 1 month after transplantation in sham-treated mouse, whereas, Olaparib treated mouse did not develop BCR-ABL1 mediated leukemia. Parp1 KO BCR-ABL1 Tg mice attenuated leukemia development and extended their survival compared with BCR-ABL1 Tg mice. In vitro experiment revealed HR activity was down-regulated by BCR-ABL1 expression in DR-GFP assay. The number of BFB generation was increased in BCR-ABL1 Tg with Parp1 KO background. The colony-forming activity of BCR-ABL1 positive HSC was totally abolished by PARP inhibition after 3 times serial replating, whereas sham-treated HSC retained repopulation activity. However, the effect of PARPi on BCR-ABL positive leukemic cell lines was controversial. Therefore, leukemic cell lines were treated with the PARPi and inhibitors toward the molecules associated with PARPi resistance. As a result, a combination of PARPi with PI3K inhibitor effectively induce cell death in PARPi resistant BCR-ABL1 positive leukemic cell lines. Conclusion and discussion: Tyrosine kinase inhibitor (TKI) is the gold standard of the therapeutic option of BCR-ABL1 positive leukemia. However, TKI monotherapy is not sufficient for complete eradication of leukemic cells. It is highly expected that molecules effectively induce cell death to leukemic cells combined with TKI. PARPi would be one of these candidates. However, PARPi could not induces efficient death in all of the cancer cells that carry the mutation of molecules associated with the HR defect. Comprehensive genetic analysis to reveal PARPi resistance is important for HRR defective cancer cells. Combination therapy of PARPi and inhibitorstoward the molecules associated with PARPi resistance would be a good therapeutic option for Ph1 positive leukemia. Disclosures No relevant conflicts of interest to declare.
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Tobin, Lisa A., Aaron P. Rapoport, Ivana Gojo, Maria R. Baer, Alan E. Tomkinson, and Feyruz V. Rassool. "DNA Ligase III Alpha and (Poly-ADP) Ribose Polymerase (PARP1) Are Therapeutic Targets in Imatinib-Resistant (IR) Chronic Myeloid Leukemia (CML)." Blood 114, no. 22 (November 20, 2009): 853. http://dx.doi.org/10.1182/blood.v114.22.853.853.
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Abstract Abstract 853 Therapy with the tyrosine kinase inhibitor imatinib, targeting the constitutively active BCR-ABL kinase has been remarkably successful in Philadelphia chromosome-positive (Ph+) CML, but resistance to tyrosine kinase inhibitors is a growing clinical problem, prompting the search for new therapeutic targets. BCR-ABL expression leads to increased reactive oxygen species (ROS), repair errors and genomic instability. We have previously shown that an error-prone alternative non-homologous end-joining (ALT NHEJ) pathway involving PARP1 and DNA ligase IIIa/XRCC1 is upregulated in Ph+ CML, providing a mechanism for the repair errors and genomic instability. To determine whether ALT NHEJ components may be novel therapeutic targets in IR CML, we characterized two IR cell lines (P210Mo7eIR, Baf3P210IR) for DSB repair abnormalities. Both IR cell lines demonstrate significantly higher levels of DSBs and NHEJ abnormalities (P<0.05) compared with their imatinib-sensitive (IS) counterparts. Notably, whereas steady state levels of the ALT NHEJ components DNA ligase IIIa and PARP1 are increased in IS P210Mo7e and Baf3P210 cells, compared with parental Mo7e and Baf3, the levels of these proteins are increased even further in the IR cells. Presence of increased DNA ligase IIIa and PARP1 levels in the IR cell lines suggests that these enzymes may be targets for therapy using the DNA ligase inhibitors that we have previously identified and PARP1 inhibitors, which have been used successfully in the treatment of cancers with DSB repair defects. Initial tests for cytotoxicity in BCR-ABL-positive cell lines and parental controls showed that the DNA ligase inhibitor L67, which specifically inhibits DNA ligase I and IIIα, is cytotoxic in BCR-ABL-positive cells and parental controls at concentrations of >10 μM, and that cytotoxicity is not influenced by BCR-ABL1 expression. Therefore, we examined the effect of a subtoxic concentration of L67 (0.3 μM) in the presence or absence of the PARP1 inhibitor Nu1025 (Calbiochem) at 50 μM in IR versus IS and parental cells. Combined treatment with L67 and Nu1025 significantly (p<0.001) reduces survival of IR cells compared with IS and parental controls, which were not significantly affected. To determine whether cells from CML patients that are resistant to imatinib are also sensitive to the combination of DNA ligase and PARP inhibitors, we next tested primary bone marrow mononuclear cells (BM MNC) from 6 CML patients with IR disease, compared with normal BM MNC. Cells from 3 of the 6 patients demonstrated a significant decrease in colony survival in response to the combination of DNA repair inhibitors, similar to the sensitivity demonstrated by the two IR cell lines studied. Interestingly, the patient demonstrating the highest sensitivity to the combination of DNA repair inhibitors had significantly increased levels of both DNA ligase IIIa and PARP1, whereas patients demonstrating less sensitivity had increased levels of either DNA ligase IIIa or PARP1, compared with normal BM MNC. Importantly, sensitivity to the DNA repair inhibitors is not correlated with mutations in BCR-ABL because the BCR-ABL mutation T315I that is found in Baf3P210IR cells when overexpressed in Baf3 cells has no effect on colony survival following drug treatment. Together, our results suggest that the process of acquiring IR may select for cells with high levels of PARP1 and DNA ligase IIIa and/or may upregulate ALT NHEJ pathways. Thus, patients with high levels of these proteins are likely to benefit from therapy using inhibitors of ALT NHEJ. Disclosures: No relevant conflicts of interest to declare.
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Truong, Sarah, Beibei Zhai, Fariba Ghaidi, Louise Ramos, Jay Joshi, Dennis Brown, Neil Sankar, et al. "Abstract 1058: Evaluation of a novel class of bifunctional DNA alkylating agent and PARP inhibitor." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1058. http://dx.doi.org/10.1158/1538-7445.am2022-1058.
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Abstract Introduction: Poly-adenosine diphosphate-ribose polymerase (PARP) inhibition is an effective, FDA-approved treatment against cancers with DNA damage repair (DDR) deficiencies, such as BRCA1 or BRCA2 mutations. PARP is a core component of single-strand break repair, so in tumors with DDR deficiencies, double-strand breaks (DSBs) and single-strand breaks (SSBs) accumulate and lead to cell death. Combining PARP inhibition with other DNA-damaging therapies, such as DNA alkylating agents, has proven to be more effective than PARP inhibition alone, as DNA alkylators can lead to the formation of DSBs. However, combination therapies often require sequential administration due to pharmacokinetic considerations and overlapping toxicities, severely limiting their clinical utility. Here, we evaluate a novel class of PARP inhibitors combined with DNA alkylating functionality, in formulation as a single molecule. Methods: PARP1 activity was determined using the Trevigen Universal Colorimetric PARP Assay Kit and PARP2 activity was determined using the BPS Bioscience PARP2 Colorimetric Assay Kit. Methylator release was evaluated by measuring the appearance of a certain degradation product. Cell cycle analysis was performed using propidium iodide staining and quantified using flow cytometry. pH2AX expression as a measure of DNA double strand breaks (DSB) was quantified by flow cytometry using an Alexa Fluor 647-conjugated anti-H2AX phospho (Ser139) antibody from BioLegend. Detection of pH2AX by western blot and immunofluorescence assays was done using anti-phospho histone H2AX (Ser139) antibody from Cell Signaling Technologies. Results: kt-4000 series compounds are potent inhibitors of both PARP1 and PARP2 with IC50 values in the low nM range, comparable to FDA-approved PARP inhibitors. The compounds release methylator in a similar manner as temozolomide, an FDA-approved DNA alkylating agent. They induce S-phase and G2/M cell cycle arrest in MCF7 cells and lead to accumulation of pH2AX by flow cytometry, western blot, and immunofluorescence assays. Conclusion: Our novel class of PARP inhibitors combined with DNA alkylating function show potent inhibition of both PARP1 and PARP2. These compounds also lead to accumulation of H2AX phosphorylation, a sensitive marker for double-strand breaks, and S-phase and G2/M cell cycle arrest. Development of these bifunctional, single molecule therapies may extend the clinical utility of PARP inhibitors to DDR proficient disease and increase efficacy for DDR deficient disease. Citation Format: Sarah Truong, Beibei Zhai, Fariba Ghaidi, Louise Ramos, Jay Joshi, Dennis Brown, Neil Sankar, John Langlands, Jeffrey Bacha, Wang Shen, Mads Daugaard. Evaluation of a novel class of bifunctional DNA alkylating agent and PARP inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1058.
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Engel, Justin, Madhavi Bandi, Antione Simoneau, Katherine Lazarides, Deepali Gotur, Truc Pham, Shangtao Liu, et al. "Abstract 2603: USP1 inhibitor synthetic lethality in BRCA1-mutant cancer is driven by PCNA ubiquitination." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2603. http://dx.doi.org/10.1158/1538-7445.am2022-2603.
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Abstract CRISPR-based functional genomic screening is a powerful approach for identifying novel classes of synthetic lethal drug targets. Here, we define the deubiquitinase USP1 as a synthetic lethal target in cancers with underlying DNA repair vulnerabilities. A highly potent and selective small molecule USP1 inhibitor conferred a viability defect in BRCA1-mutant, but not WT cell lines by activating replication stress. Genome-wide CRISPR screening uncovered RAD18 and UBE2K, which promote PCNA mono- and poly-ubiquitination respectively, as key mediators of USP1-BRCA1 dependency. Increased cellular mono- and poly-ubiquitination reduced PCNA protein levels, and restoration of PCNA protein expression rescued USP1 inhibitor sensitivity. USP1 dependency is associated with upregulated RAD18 and UBE2K expression, suggesting that elevated PCNA ubiquitination in the context of BRCA1 deficiency mediates USP1 synthetic lethality. Interestingly, USP1, but not PARP1 inhibition, elicited a viability defect in a subset of BRCA1/2 WT lung cancer cell lines, indicative of novel synthetic lethal interactions unique to USP1. Moreover, dual inhibition of PARP1 and USP1 are strongly synergistic in PARP1 inhibitor-responsive cell line models. Strong in vivo anti-tumor activity across multiple tumor models was demonstrated with USP1 inhibition alone and in combination with the PARP1 inhibitor olaparib. Our studies suggest that USP1 and PARP1 inhibitors target BRCA1-mutant cancer though distinct yet synergistic mechanisms. As such, USP1 inhibitors may provide novel treatment strategies for PARP1 inhibitor-resistant and -naïve BRCA1-mutant cancer. Citation Format: Justin Engel, Madhavi Bandi, Antione Simoneau, Katherine Lazarides, Deepali Gotur, Truc Pham, Shangtao Liu, Samuel Meier, Ashley Choi, Hongxiang Zhang, Binzhang Shen, Fang Li, Douglas Whittington, Shanzhong Gong, Xuewen Pan, Yi Yu, Lina Gu, Scott Throner, John Maxwell, Yingnan Chen, Alan Huang, Jannik Andersen, Tianshu Feng. USP1 inhibitor synthetic lethality in BRCA1-mutant cancer is driven by PCNA ubiquitination [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2603.
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Guibbal, Florian, Samantha L. Hopkins, Anna Pacelli, Patrick G. Isenegger, Michael Mosley, Julia Baguña Torres, Gemma M. Dias, et al. "[18F]AZD2461, an Insight on Difference in PARP Binding Profiles for DNA Damage Response PET Imaging." Molecular Imaging and Biology 22, no. 5 (April 27, 2020): 1226–34. http://dx.doi.org/10.1007/s11307-020-01497-6.
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Abstract Background Poly (ADP-ribose) polymerase (PARP) inhibitors are extensively studied and used as anti-cancer drugs, as single agents or in combination with other therapies. Most radiotracers developed to date have been chosen on the basis of strong PARP1–3 affinity. Herein, we propose to study AZD2461, a PARP inhibitor with lower affinity towards PARP3, and to investigate its potential for PARP targeting in vivo. Methods Using the Cu-mediated 18F-fluorodeboronation of a carefully designed radiolabelling precursor, we accessed the 18F-labelled isotopologue of the PARP inhibitor AZD2461. Cell uptake of [18F]AZD2461 in vitro was assessed in a range of pancreatic cell lines (PSN-1, PANC-1, CFPAC-1 and AsPC-1) to assess PARP expression and in vivo in xenograft-bearing mice. Blocking experiments were performed with both olaparib and AZD2461. Results [18F]AZD2461 was efficiently radiolabelled via both manual and automated procedures (9 % ± 3 % and 3 % ± 1 % activity yields non-decay corrected). [18F]AZD2461 was taken up in vivo in PARP1-expressing tumours, and the highest uptake was observed for PSN-1 cells (7.34 ± 1.16 %ID/g). In vitro blocking experiments showed a lesser ability of olaparib to reduce [18F]AZD2461 binding, indicating a difference in selectivity between olaparib and AZD2461. Conclusion Taken together, we show the importance of screening the PARP selectivity profile of radiolabelled PARP inhibitors for use as PET imaging agents.
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Wray, Justin, Elizabeth A. Williamson, Sudha B. Singh, Yuehan Wu, Christopher R. Cogle, David M. Weinstock, Yu Zhang, et al. "PARP1 is required for chromosomal translocations." Blood 121, no. 21 (May 23, 2013): 4359–65. http://dx.doi.org/10.1182/blood-2012-10-460527.
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Tutt, ANJ. "Abstract ES6-4: Parp inhibitors for brca1/2mutation associated breast cancer." Cancer Research 82, no. 4_Supplement (February 15, 2022): ES6–4—ES6–4. http://dx.doi.org/10.1158/1538-7445.sabcs21-es6-4.
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Abstract More than 15 years ago we and others showed the use of potent PARP1 inhibitors (PARPi), that both inhibit the catalytic activity of the PARP1 enzyme and trap PARP1 onto DNA, generate a “synthetic lethal” interaction with the malignant cell specific loss of function of genes crucial for homologous recombination (HR) gene function. This phenomenon has now been exploited with therapeutic intent in several contexts leading to approved single agent PARPi treatments for advanced forms of ovarian, prostate, pancreatic and breast cancers. These approvals have in large part been associated a biomarker requirement for evidence of loss of function of HR. Recently a number of trials have investigated PARPi in a (neo)adjuvant breast cancer treatment (NACT) setting in patients with (or enriched for) HR deficiency. These have included phase II neoadjuvant PARPi studies such as the NeoTALA study using single agent talazoparib in germline BRCA1 and BRCA2 mutation carriers and the combination chemotherapy and olaparib therapy studies GeparOLA and PARTNER, enriched for HR deficient breast cancer, that have reported important signals with regard efficacy and tolerability. Two recent phase III trials have influenced recent early breast cancer treatment guidelines. These are the BrighTNess trial in the neoadjuvant setting and OlympiA in the post-(neo)adjuvant setting. BrighTNess recruited patients with biologically heterogeneous triple negative breast cancer (TNBC) and used the weak PARP1 trapping PARPi veliparib and OlympiA restricted eligibility to patients with the germline “pathogenic” or “likely pathogenic” mutation in BRCA1 or BRCA2 but included patients with hormone receptor positive breast cancer. BrighTNess did not show convincing evidence of benefit to the addition of veliparib to standard of care in TNBC NACT but has shown the benefit to the addition of carboplatin to sequential paclitaxel-AC NACT with significant improvements in event free survival (HR 0.57 ) compared to sequential paclitaxel-AC alone. OlympiA has reported following an interim analysis showing 12 months of olaparib in the post-(neo)adjuvant chemotherapy setting improves both invasive disease free and distant disease free survival by approximately 40% with highly statistically significant hazard ratios of 0.58 and 0.57 respectively that met pre-specified early stopping boundaries. The publication of results for OlympiA has led to rapid updates of both genetic testing and treatment international guidelines for BRCA1 and BRCA2 mutation associated breast cancer to include use of olaparib in patients meeting the eligibility criteria for the trial. The lecture will both explore the data and the implications for practice of the adoption of these guidelines and some of the ongoing questions to be addressed by ongoing clinical trial and translational research initiatives. Citation Format: ANJ Tutt. Parp inhibitors for brca1/2mutation associated breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr ES6-4.