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1
Sipos, Ádám, Eszter Szennyes, Nikolett Éva Hajnal, Sándor Kun, Katalin E. Szabó, Karen Uray, László Somsák, Tibor Docsa e Éva Bokor. "Dual-Target Compounds against Type 2 Diabetes Mellitus: Proof of Concept for Sodium Dependent Glucose Transporter (SGLT) and Glycogen Phosphorylase (GP) Inhibitors". Pharmaceuticals 14, n. 4 (15 aprile 2021): 364. http://dx.doi.org/10.3390/ph14040364.
Testo completoAbstract (sommario):
A current trend in the quest for new therapies for complex, multifactorial diseases, such as diabetes mellitus (DM), is to find dual or even multi-target inhibitors. In DM, the sodium dependent glucose cotransporter 2 (SGLT2) in the kidneys and the glycogen phosphorylase (GP) in the liver are validated targets. Several (β-D-glucopyranosylaryl)methyl (het)arene type compounds, called gliflozins, are marketed drugs that target SGLT2. For GP, low nanomolar glucose analogue inhibitors exist. The purpose of this study was to identify dual acting compounds which inhibit both SGLTs and GP. To this end, we have extended the structure-activity relationships of SGLT2 and GP inhibitors to scarcely known (C-β-D-glucopyranosylhetaryl)methyl arene type compounds and studied several (C-β-D-glucopyranosylhetaryl)arene type GP inhibitors against SGLT. New compounds, such as 5-arylmethyl-3-(β-D-glucopyranosyl)-1,2,4-oxadiazoles, 5-arylmethyl-2-(β-D-glucopyranosyl)-1,3,4-oxadiazoles, 4-arylmethyl-2-(β-D-glucopyranosyl)pyrimidines and 4(5)-benzyl-2-(β-D-glucopyranosyl)imidazole were prepared by adapting our previous synthetic methods. None of the studied compounds exhibited cytotoxicity and all of them were assayed for their SGLT1 and 2 inhibitory potentials in a SGLT-overexpressing TSA201 cell system. GP inhibition was also determined by known methods. Several newly synthesized (C-β-D-glucopyranosylhetaryl)methyl arene derivatives had low micromolar SGLT2 inhibitory activity; however, none of these compounds inhibited GP. On the other hand, several (C-β-D-glucopyranosylhetaryl)arene type GP inhibitor compounds with low micromolar efficacy against SGLT2 were identified. The best dual inhibitor, 2-(β-D-glucopyranosyl)-4(5)-(2-naphthyl)-imidazole, had a Ki of 31 nM for GP and IC50 of 3.5 μM for SGLT2. This first example of an SGLT-GP dual inhibitor can prospectively be developed into even more efficient dual-target compounds with potential applications in future antidiabetic therapy.
2
Gesinski, Dayna, e Sonali Kurup. "Abstract 5337: Design, synthesis and evaluation of dual-targeted mEGFR and AURK inhibitors as anticancer agents". Cancer Research 83, n. 7_Supplement (4 aprile 2023): 5337. http://dx.doi.org/10.1158/1538-7445.am2023-5337.
Testo completoAbstract (sommario):
Abstract Mutant epidermal growth factor receptor (mEGFR) inhibitors constitute the recommended therapy for mEGFR-positive cancers. However, resistance has developed to mEGFR inhibitors due to newer mutations within the enzyme pocket and redundant signaling pathways that bypass mEGFR inhibition. Recent studies have shown that resistance to mEGFR inhibitors could be overcome if given in combination with aurora kinase (AURK) inhibitors. Dual EGFR/AURK kinase inhibitors provide a novel approach to overcome resistance to EGFR inhibitors. In a previous study, Kurup et al. identified 1 as a nanomolar mEGFR inhibitor. Using a structure-based design approach, novel analogs of 1 that incorporated varied sidechains for dual mEGFR and AURK inhibition were designed. The synthesis of the target compounds involved microwave-assisted, copper and palladium catalyzed coupling reactions. This study led to the identification of dual-targeted mEGFR/AURKA and mEGFR/AURKB inhibitors, and compounds with sub-micromolar cellular potencies. The design, synthesis, kinase inhibitory activities and anticancer effects of these novel analogs will be presented. Structure-activity relationships for mEGFR, AURKA and AURKB inhibition will be defined. Citation Format: Dayna Gesinski, Sonali Kurup. Design, synthesis and evaluation of dual-targeted mEGFR and AURK inhibitors as anticancer agents. [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 5337.
3
Kim, Min-Jeong, Sarita Pandit e Jun-Goo Jee. "Discovery of Kinase and Carbonic Anhydrase Dual Inhibitors by Machine Learning Classification and Experiments". Pharmaceuticals 15, n. 2 (16 febbraio 2022): 236. http://dx.doi.org/10.3390/ph15020236.
Testo completoAbstract (sommario):
A multi-target small molecule modulator is advantageous for treating complicated diseases such as cancers. However, the strategy and application for discovering a multi-target modulator have been less reported. This study presents the dual inhibitors for kinase and carbonic anhydrase (CA) predicted by machine learning (ML) classifiers, and validated by biochemical and biophysical experiments. ML trained by CA I and CA II inhibitor molecular fingerprints predicted candidates from the protein-specific bioactive molecules approved or under clinical trials. For experimental tests, three sulfonamide-containing kinase inhibitors, 5932, 5946, and 6046, were chosen. The enzyme assays with CA I, CA II, CA IX, and CA XII have allowed the quantitative comparison in the molecules’ inhibitory activities. While 6046 inhibited weakly, 5932 and 5946 exhibited potent inhibitions with 100 nM to 1 μM inhibitory constants. The ML screening was extended for finding CAs inhibitors of all known kinase inhibitors. It found XMU-MP-1 as another potent CA inhibitor with an approximate 30 nM inhibitory constant for CA I, CA II, and CA IX. Differential scanning fluorimetry confirmed the direct interaction between CAs and small molecules. Cheminformatics studies, including docking simulation, suggest that each molecule possesses two separate functional moieties: one for interaction with kinases and the other with CAs.
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Bošković, Jelena, Vladimir Dobričić, Marija Mihajlović, Jelena Kotur-Stevuljević e Olivera Čudina. "Synthesis, Evaluation of Enzyme Inhibition and Redox Properties of Potential Dual COX-2 and 5-LOX Inhibitors". Pharmaceuticals 16, n. 4 (6 aprile 2023): 549. http://dx.doi.org/10.3390/ph16040549.
Testo completoAbstract (sommario):
Various dual inhibitors of COX-2 and 5-LOX enzymes have been developed so far in order to obtain more effective and safer anti-inflammatory drugs. The aim of this study was to design and synthesize new dual COX-2 and 5-LOX inhibitors, and to evaluate their enzyme inhibition potential and redox properties. Thirteen compounds (1–13) were designed taking into account structural requirements for dual COX-2 and 5-LOX inhibition and antioxidant activity, synthesized, and structurally characterized. These compounds can be classified as N-hydroxyurea derivatives (1, 2 and 3), 3,5-di-tert-butylphenol derivatives (4, 5, 6, 7 and 13), urea derivatives (8, 9 and 10) and “type B hydroxamic acids” (11 and 12). COX-1, COX-2 and 5-LOX inhibitory activities were evaluated using fluorometric inhibitor screening kits. The evaluation of the redox activity of newly synthesized compounds was performed in vitro in the human serum pool using redox status tests. The prooxidative score, the antioxidative score and the oxy-score were calculated. Seven out of thirteen synthesized compounds (1, 2, 3, 5, 6, 11 and 12) proved to be dual COX-2 and 5-LOX inhibitors. These compounds expressed good COX-2/COX-1 selectivity. Moreover, dual inhibitors 1, 3, 5, 11 and 12 showed good antioxidant properties.
5
Wang, Q. May, Robert B. Johnson, Louis N. Jungheim, Jeffrey D. Cohen e Elcira C. Villarreal. "Dual Inhibition of Human Rhinovirus 2A and 3C Proteases by Homophthalimides". Antimicrobial Agents and Chemotherapy 42, n. 4 (1 aprile 1998): 916–20. http://dx.doi.org/10.1128/aac.42.4.916.
Testo completoAbstract (sommario):
ABSTRACT The 2A and 3C proteases encoded by human rhinoviruses (HRVs) are attractive targets for antiviral drug development due to their important roles in viral replication. Homophthalimides were originally identified as inhibitors of rhinovirus 3C protease through our screening effort. Previous studies have indicated that the antiviral activity of certain homophthalimides exceeded their in vitro inhibitory activity against the viral 3C protease, suggesting that an additional mechanism might be involved. Reported here is the identification of homophthalimides as potent inhibitors for another rhinovirus protease, designated 2A. Several homophthalimides exhibit time-dependent inhibition of the 2A protease in the low-micromolar range, and enzyme-inhibitor complexes were identified by mass spectrometry. Compound LY343814, one of the most potent inhibitors against HRV14 2A protease, had an antiviral 50% inhibitory concentration of 4.2 μM in the cell-based assay. Our data reveal that homophthalimides are not only 3C but also 2A protease inhibitors in vitro, implying that the antiviral activity associated with these compounds might result from inactivation of both 2A and 3C proteases in vivo. Since the processing of the viral polyprotein is hierarchical, dual inhibition of the two enzymes may result in cooperative inhibition of viral replication. On the basis of the current understanding of their enzyme inhibitory mechanism, homophthalimides, as a group of novel nonpeptidic antirhinovirus agents, merit further structure-action relationship studies.
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Lu, Haiying, Lan Bai, Yanping Zhou, Yongping Lu, Zhongliang Jiang e Jianyou Shi. "Recent Study of Dual HDAC/PARP Inhibitor for the Treatment of Tumor". Current Topics in Medicinal Chemistry 19, n. 12 (30 luglio 2019): 1041–50. http://dx.doi.org/10.2174/1568026619666190603092407.
Testo completoAbstract (sommario):
The occurrence and development of tumors are closely related to epigenetic instability which modulates gene expression through DNA methylation, histone modification, chromatin remodeling, and RNA-related silencing. Histone deacetylase (HDAC) and poly (ADP-ribose) polymerase (PARP) are targets of epigenetic regulation. Over the years, a large number of studies have shown that HDAC inhibitors and PARP inhibitors have synergistic effects in the treatment of tumors, and there are reports of related dual HDAC/PARP inhibitors. This review will give a brief summary of the synergistic mechanisms of HDAC inhibitors and PARP inhibitors and introduce the design of the first dual HDAC/PARP inhibitor, which may guide the design of more dual HDAC/PARP inhibitors for the treatment of tumors.
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Wen, Hui, Wen Qin, Guangzhong Yang e Yanshen Guo. "Design and Synthesis of Arylamidine Derivatives as Serotonin/Norepinephrine Dual Reuptake Inhibitors". Molecules 24, n. 3 (30 gennaio 2019): 497. http://dx.doi.org/10.3390/molecules24030497.
Testo completoAbstract (sommario):
To improve the in vivo antidepressant activity of previously reported serotonin (5-HT) and norepinephrine (NE) dual reuptake inhibitors, three series of arylamidine derivatives were designed and synthesized. The in vitro 5-HT and NE reuptake inhibitory activities of these compounds were evaluated, and compound II-5 was identified as the most potent 5-HT (IC50 = 620 nM) and NE (IC50 = 10 nM) dual reuptake inhibitor. Compound II-5 exhibited potent antidepressant activity in the rat tail suspension test and showed an acceptable safety profile in a preliminary acute toxicity test in mice. Our results show that these arylamidine derivatives exhibit potent 5-HT/NE dual reuptake inhibition and should be explored further as antidepressant drug candidates.
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Vest, Rebekah S., Kurtis D. Davies, Heather O'Leary, J. David Port e K. Ulrich Bayer. "Dual Mechanism of a Natural CaMKII Inhibitor". Molecular Biology of the Cell 18, n. 12 (dicembre 2007): 5024–33. http://dx.doi.org/10.1091/mbc.e07-02-0185.
Testo completoAbstract (sommario):
Ca2+/calmodulin (CaM)-dependent protein kinase II (CaMKII) is a major mediator of cellular Ca2+ signaling. Several inhibitors are commonly used to study CaMKII function, but these inhibitors all lack specificity. CaM-KIIN is a natural, specific CaMKII inhibitor protein. CN21 (derived from CaM-KIIN amino acids 43–63) showed full specificity and potency of CaMKII inhibition. CNs completely blocked Ca2+-stimulated and autonomous substrate phosphorylation by CaMKII and autophosphorylation at T305. However, T286 autophosphorylation (the autophosphorylation generating autonomous activity) was only mildly affected. Two mechanisms can explain this unusual differential inhibitor effect. First, CNs inhibited activity by interacting with the CaMKII T-site (and thereby also interfered with NMDA-type glutamate receptor binding to the T-site). Because of this, the CaMKII region surrounding T286 competed with CNs for T-site interaction, whereas other substrates did not. Second, the intersubunit T286 autophosphorylation requires CaM binding both to the “kinase” and the “substrate” subunit. CNs dramatically decreased CaM dissociation, thus facilitating the ability of CaM to make T286 accessible for phosphorylation. Tat-fusion made CN21 cell penetrating, as demonstrated by a strong inhibition of filopodia motility in neurons and insulin secrection from isolated Langerhans' islets. These results reveal the inhibitory mechanism of CaM-KIIN and establish a powerful new tool for dissecting CaMKII function.
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Lambert, Que T., Stuart W. Ember, Muhammad Ayaz, Harshani R. Lawrence, Norbert Berndt, Steven Gunawan, Nicholas J. Lawrence, Ernst Schönbrunn e Gary W. Reuther. "Single Molecule Dual JAK2-BET Inhibition As an MPN Therapeutic". Blood 126, n. 23 (3 dicembre 2015): 2826. http://dx.doi.org/10.1182/blood.v126.23.2826.2826.
Testo completoAbstract (sommario):
Abstract The optimism of anti-JAK2 therapy for the treatment of MPNs is largely based on the ability of JAK inhibitors to improve MPN patient constitutional symptoms. Unfortunately, such inhibitors are generally unable to induce remission or even allele burden, suggesting anti-JAK2 based therapies need refinement and optimization. Combination therapies continue to be widely investigated, however, such approaches could have significant complications when translating to patients. These include the difficulty determining proper dosing of each drug in combination in patients, the cost of treatment, and issues with combining drugs developed by different pharmaceutical companies. Recently, we and others have identified anti-BET bromodomain inhibitory properties of various kinase inhibitors, including the JAK2 inhibitors TG101209 and TG101308. Bromodomains are protein-protein interaction motifs that bind to acetylated lysine and, for example, can play roles in regulating gene expression by binding acetylated histones. These dual kinase-BET inhibitors bind to the acetylated lysine-binding pocket of BET bromodomains and thus inhibit the function of such domains. Importantly, cancer cells appear to be particularly sensitive to BET inhibitors compared to normal cells. Combining a BET inhibitor and a JAK2 inhibitor has been shown to be more effective against MPN cells than JAK2 inhibition alone. Our recent identification of dual kinase-BET inhibitors allows for the rational design of drugs with polypharmacology to inhibit more than one class of targets. To this end, we have optimized small molecules for dual anti-JAK2 and anti-BET activity. MA2-014 is a chemical derivative of TG101209 that exhibits similar anti-JAK2 activity, but about ten-fold improved anti-BET activity than TG101209. In fact, the activity of MA2-014 to target BET domains is similar to the prototypical BET inhibitor JQ1. For example, the IC50s of MA2-014 and JQ1 against the second bromodomain of the BET family member BRD4 are each about 20 nM. MA2-014 retains comparable biochemical activity against JAK2 as TG101209 and ruxolitinib (IC50s of low single digit nM, ~0.5 to 3 nM). In MPN cells, however, the ability of MA2-014 to inhibit JAK2-V617F signaling in MPN cells, as measured by P-STAT5, is about ten-fold improved over TG101209, and is comparable to ruxolitinib. Likewise, the ability of MA2-014 to inhibit the expression of c-Myc, which is widely used as a biomarker for BET inhibition, is about ten-fold better than TG101209 in MPN cells. The IC50 for MA2-014 for growth of Uke1 MPN cells is about 200 nM, compared to 500 nM for TG101209. Taken together, these data suggest that MA2-014 is a dual JAK2-BET inhibitor that exhibits superior BET inhibitory activity with similar if not better cellular JAK2 inhibitory activity than TG101209. MA2-014 efficiently inhibited the erythropoietin independent erythroid colony formation of myeloid progenitors from MPN patients, which is a hallmark of these cells and is widely used to test MPN therapeutics. The IC50 of MA2-014 in this assay is 50 nM, essentially identical to ruxolitinib, the only FDA approved JAK2 inhibitor for MPNs. The IC50 of TG101209 to inhibit this colony formation of primary MPN cells is 200 nM, four times greater than MA2-014. Interestingly, JAK2-V617F-driven MPN model cells that are resistant to ruxolitinib retained sensitivity to MA2-014. The IC50s of ruxolitinib and MA2-014 against the growth of BaF3-JAK2-V617F cells are about 100 nM. However, the same cells that are resistant to ruxolitinib (IC50 >2000 nM) remain sensitive to MA2-014 (IC50 of 240 nM). Finally, in long-term culture assays, we have determined that JAK2-V617F driven MPN Uke1 cells are not able to become resistant to MA2-014 as readily as they do to TG101209 or ruxolitinib. These data suggest MA2-014 may be more resilient to drug resistance, the major hurdle in the clinical effectiveness of JAK2 inhibitors. Collectively, our work demonstrates that rationally-designed polypharmacology may be a novel approach to develop effective therapeutics for cancer, especially diseases that are driven by aberrant kinase signaling and are also sensitive to BET inhibition, as exemplified by MPNs. The use of such an optimized polypharmacologic therapeutic may provide the benefits of combination therapy with fewer complications associated with clinical development. Disclosures No relevant conflicts of interest to declare.
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Dyer, Richard D., e David T. Connor. "Dual Inhibitors Of Prostaglandin And Leukotriene Biosynthesis". Current Pharmaceutical Design 3, n. 5 (1997): 463–72. http://dx.doi.org/10.2174/138161280305221010095741.
Testo completoAbstract (sommario):
One of the most promising approaches for minimizing the side effects of nonsteroidal antiinflammatory drugs (NSAIDs) is to concurrently inhibit the activities of both 5-lipoxygenase (5-LO) and cyclooxygenase (CO). Many such dual inhibitors of prostaglandin (PG) and leukotriene (LT) production in vitro have been described but, despite intense pharmaceutical research efforts, the translation of this in vitro activity into in vivo efficacy has proven difficult. Chemical modification of one series of inhibitors, the 2,6-di-tert butylphenols, has provided a variety of dual inhibitors with antiinflammatory efficacy and superior gastrointestinal (GI) safety. Whereas optimization of the di-t-butylphenols for in vitro activity, inhibitory specificity, oral availability and antiinflammatory efficacy resulted in the identification of Cl-1004 and other clincal candidates, optimization of other chemical series typically resulted in dual inhibitors with potent in vitro effects but little in vivo activity. The development of several dual inhibitors, including tepoxalin, tebufelone and CI-986, has been limited by drug metabolism issues. Translation of the attractive preclinical antiinflammatory and safety profile of dual inhibitors to the clinical arena awaits the completion of thorough clinical studies, such as those currently underway with CI-1004.
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Omidkhah, Negar, e Razieh Ghodsi. "NO-HDAC dual inhibitors". European Journal of Medicinal Chemistry 227 (gennaio 2022): 113934. http://dx.doi.org/10.1016/j.ejmech.2021.113934.
Testo completo
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Dong, Hang, Hao Yin, Chunlong Zhao, Jiangying Cao, Wenfang Xu e Yingjie Zhang. "Design, Synthesis and Biological Evaluation of Novel Osimertinib-Based HDAC and EGFR Dual Inhibitors". Molecules 24, n. 13 (29 giugno 2019): 2407. http://dx.doi.org/10.3390/molecules24132407.
Testo completoAbstract (sommario):
Herein a novel series of histone deacetylases (HDACs) and epidermal growth factor receptor (EGFR) dual inhibitors were designed and synthesized based on the structure of the approved EGFR inhibitor osimertinib (AZD9291). Among them, four compounds 5D, 5E, 9D and 9E exhibited more potent total HDAC inhibition than the approved HDAC inhibitor SAHA. However, these compounds only showed moderate to low inhibitory potency towards EGFR with compounds 5E and 9E possessing IC50 values against EGFRWT and EGFRT790M in the micromolar range. 3-[4,5-dimethyl-2-thiazolyl]-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay revealed the potent antiproliferative activities of compounds 5D, 5E, 9D and 9E, among which 9E was even more potent against HeLa, MDA-MB-231, MDA-MB-468, HT-29 and KG-1 cell lines than SAHA and AZD9291. Further selectivity profile of 9E showed that this compound was not active against other 13 cancer-related kinases and two epigenetic targets lysine specific demethylase 1 (LSD1) and bromodomain-containing protein 4 (BRD4). These results support further structural modification of 9E to improve its EGFR inhibitory activity, which will lead to more potent and balanced HDAC and EGFR dual inhibitors as anticancer agents.
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Rogers, Brianne, Nicholas Rohde, Justin Mikitaroff, Joshua Matson, Samantha Satawa, Felix Amissah e Sonali Kurup. "Abstract 5339: 4-Amino-N-phenylbenzamides as dual-targeted mEGFR and AURK inhibitors and anticancer agents". Cancer Research 83, n. 7_Supplement (4 aprile 2023): 5339. http://dx.doi.org/10.1158/1538-7445.am2023-5339.
Testo completoAbstract (sommario):
Abstract Small molecule, mutant epidermal growth factor receptor kinase (mEGFR) inhibitors are rendered ineffective in NSCLC due to mutations within the enzyme binding sites and redundant signaling pathways. The mEGFR inhibitors were found to retain their anticancer effects in NSCLC cells if given concurrently with AURK inhibitors. Dual-targeted small molecules designed to inhibit both mEGFR and AURK could demonstrate improved anticancer effects compared to monotargeted mEGFR inhibitors. We conducted molecular modeling studies to determine if there were similarities between the kinase pockets of mEGFR and AURK that could be exploited to develop dual-targeted mEGFR and AURK inhibitors. An overlap was observed for the active and allosteric sites of the kinase pocket for mEGFR and AURK. A series of compounds were synthesized and evaluated against mEGFR, AURKA, and AURKB. We found the kinase inhibitory profile to vary significantly depending on the substitution pattern ranging from selective mEGFR inhibitors to dual mEGFR and AURK inhibitors. The 4-substituted amino-N-phenylbenzamides were identified as dual mEGFR/AURK inhibitors. Dual mEGFR/AURK inhibitors demonstrated varied modes of binding within mEGFR and AURK. The most potent dual mEGFR and AURK inhibitors displayed nanomolar inhibition of mEGFR and AURK, and single-digit micromolar inhibition of non-small cell lung cancer cells. Target compounds were further evaluated in a 96-kinase screening assay and demonstrated selectivity for target kinases. The synthesis, structure-activity relationship (SAR) analysis and anticancer effects will be presented and discussed. Citation Format: Brianne Rogers, Nicholas Rohde, Justin Mikitaroff, Joshua Matson, Samantha Satawa, Felix Amissah, Sonali Kurup. 4-Amino-N-phenylbenzamides as dual-targeted mEGFR and AURK inhibitors and anticancer agents. [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 5339.
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KUMAR, Priyadarsini, e Donal A. WALSH. "A dual-specificity isoform of the protein kinase inhibitor PKI produced by alternate gene splicing". Biochemical Journal 362, n. 3 (8 marzo 2002): 533–37. http://dx.doi.org/10.1042/bj3620533.
Testo completoAbstract (sommario):
We have previously shown that the protein kinase inhibitor β (PKIβ) form of the cAMP-dependent protein kinase inhibitor exists in multiple isoforms, some of which are specific inhibitors of the cAMP-dependent protein kinase, whereas others also inhibit the cGMP-dependent enzyme [Kumar, Van Patten and Walsh (1997), J. Biol. Chem. 272, 20011–20020]. We have now demonstrated that the switch from a cAMP-dependent protein kinase (PKA)-specific inhibitor to one with dual specificity arises as a consequence of alternate gene splicing. We have confirmed using bacterially produced pure protein that a single inhibitor species has dual specificity for both PKA and cGMP-dependent protein kinase (PKG), inhibiting each with very high and closely similar inhibitory potencies. The gene splicing converted a protein with 70 amino acids into one of 109 amino acids, and did not change the inhibitory potency to PKA, but changed it from a protein that had no detectable PKG inhibitory activity to one that now inhibited PKG in the nanomolar range.
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Mao, Beibei, Qi Zhang, Li Ma, Dong-Sheng Zhao, Pan Zhao e Peizheng Yan. "Overview of Research into mTOR Inhibitors". Molecules 27, n. 16 (19 agosto 2022): 5295. http://dx.doi.org/10.3390/molecules27165295.
Testo completoAbstract (sommario):
The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that belongs to the phosphoinositide 3-kinase (PI3K)-related kinase (PIKK) family. The kinase exists in the forms of two complexes, mTORC1 and mTORC2, and it participates in cell growth, proliferation, metabolism, and survival. The kinase activity is closely related to the occurrence and development of multiple human diseases. Inhibitors of mTOR block critical pathways to produce antiviral, anti-inflammatory, antiproliferative and other effects, and they have been applied to research in cancer, inflammation, central nervous system diseases and viral infections. Existing mTOR inhibitors are commonly divided into mTOR allosteric inhibitors, ATP-competitive inhibitors and dual binding site inhibitors, according to their sites of action. In addition, there exist several dual-target mTOR inhibitors that target PI3K, histone deacetylases (HDAC) or ataxia telangiectasia mutated and Rad-3 related (ATR) kinases. This review focuses on the structure of mTOR protein and related signaling pathways as well as the structure and characteristics of various mTOR inhibitors. Non-rapalog allosteric inhibitors will open new directions for the development of new therapeutics specifically targeting mTORC1. The applications of ATP-competitive inhibitors in central nervous system diseases, viral infections and inflammation have laid the foundation for expanding the indications of mTOR inhibitors. Both dual-binding site inhibitors and dual-target inhibitors are beneficial in overcoming mTOR inhibitor resistance.
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Sun, Xuefeng, Ningning Fan, Weisi Xu, Yixing Sun, Xin Xie, Ying Guo, Liying Ma, Junyi Liu e Xiaowei Wang. "Design, synthesis and biological evaluation of caffeoyl benzanilides as dual inhibitors of HIV integrase and CCR5". MedChemComm 7, n. 10 (2016): 2028–32. http://dx.doi.org/10.1039/c6md00311g.
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Cheng, Haoyang, Yanruisheng Shao e Yan Zhang. "Research Progress of PARP-1 Related Dual Target Inhibitors". Highlights in Science, Engineering and Technology 6 (27 luglio 2022): 111–20. http://dx.doi.org/10.54097/hset.v6i.952.
Testo completoAbstract (sommario):
The treatment of cancer has always been based on surgery, radiotherapy and chemotherapy, but the cure rate of these methods is often very low and the side effects on patients are very serious. With the gradual understanding of cancer, targeted drug therapy has gradually attracted the attention of the scientific community. Initially, doctors used some single target inhibitors as targeted drugs for tumor treatment. However, with the increasing of single drug resistance and side effects, the problems of single drug resistance and side effects gradually emerge in clinical practice. Poly ADP-ribose polymerase-1 inhibitor (parp-1i) can inhibit DNA damage and repair in cells, so it is used as a kind of targeted drugs for tumor therapy. At a time when single target drugs are facing challenges, scientists have turned their attention to dual target inhibitors related to parp-1i with stronger effects. In this paper, we focus on the challenges faced by PARP-1 related single target inhibitors and the research progress of HDAC inhibitors or BRD4 inhibitors combined with PARP-1 inhibitors as double target inhibitors. It was found out that some new synthesized dual PARP/HDAC inhibitors and PARP/BRD4 inhibitors have shown great anticancer activities in vitro experiments, including compound I-8 and II-16 Therefore, this review confirmsthat PARP-related dual target inhibitors can be a promising approach to treat cancer cell.
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Hou, Xiaodan, Honghua Yan, Xin Zhang, Weidong Qian, Dong Chen, Zhihua Ren e Youzhi Tong. "Abstract 6509: GT0486, a novel mTORC1/2 dual inhibitor, exhibits synergistic antitumor efficacy in combination with BTK inhibitors". Cancer Research 84, n. 6_Supplement (22 marzo 2024): 6509. http://dx.doi.org/10.1158/1538-7445.am2024-6509.
Testo completoAbstract (sommario):
Abstract Mammalian target of rapamycin (mTOR), a serine/threonine kinase, is the central signal molecule in regulating cell growth, metabolism, angiogenesis, and survival. The first generation of mTOR inhibitors specifically inhibit mTORC1 but are insensitive to mTORC2 and cannot eliminate the downstream signaling cascade in cancer. GT0486, a second-generation mTORC1/2 dual inhibitor, can selectively suppress mTOR kinase activity while has no inhibitory effect on other kinase receptors. We investigate the anti-tumor efficacy of GT0486 in a variety of tumor cells and xenograft animal models in vitro and in vivo. The combination effects of GT0486 and BTKi (BTK inhibitor) were also evaluated. Compared with other mTOR inhibitors (GDC-0349, AZD-2014, Rapamycin, GDC-0941, and CC-223), GT0486 exhibits the stronger inhibitory activity on human tumor cells, such as U87(glioma), PC-3(prostate cancer), MDA-MB-468(breast cancer) and Huh-7(liver cancer). In B-cell lymphoma, compared with the CC-223, GT0486 shows greater inhibitory potency against TMD8, DoHH2 and WSU-DLCL2, with IC50 values of 85nM, 96nM and 83nM, respectively. Moreover, in the U87 and the PC-3 xenograft animal models, GT0486 strongly reduced tumor growth in dose dependent manner. High synergistic effects were observed with GT0486 in combination with BTK inhibitors, including Acalabrutinib, Ibrutinib, Zanubrutinib and Orelabrutinib in the BTKi sensitive TMD8 cells. In BTKi resistant DoHH2 cells, GT0486 also enhanced the drug sensitivity of BTKi. The possible biomarkers on the synergistic mechanism were further studied. GT0486 improves the role of BTKi on cell cycle arrest in phase G1. At the same time, the phosphorylation levels of mTOR downstream effectors AKT, 4EBP1 and S6 were dose-dependently downregulated after GT0486 treatment, and a significant reduction were observed when combined with BTKi. These results demonstrate that GT0486 is a promising dual mTOR1/2 inhibitor, which is currently undergoing clinical phase I study in China for the treatment of solid tumors. Strong synergistic effects observed with GT0486 in combination with BTKi in this study might open a way for a novel treatment strategy in clinical trials. Citation Format: Xiaodan Hou, Honghua Yan, Xin Zhang, Weidong Qian, Dong Chen, Zhihua Ren, Youzhi Tong. GT0486, a novel mTORC1/2 dual inhibitor, exhibits synergistic antitumor efficacy in combination with BTK inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6509.
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Weisberg, Ellen, Lolita Banerji, Renee D. Wright, Rosemary Barrett, Arghya Ray, Daisy Moreno, Laurence Catley et al. "Potentiation of antileukemic therapies by the dual PI3K/PDK-1 inhibitor, BAG956: effects on BCR-ABL– and mutant FLT3-expressing cells". Blood 111, n. 7 (1 aprile 2008): 3723–34. http://dx.doi.org/10.1182/blood-2007-09-114454.
Testo completoAbstract (sommario):
AbstractMediators of PI3K/AKT signaling have been implicated in chronic myeloid leukemia (CML) and acute myeloid leukemia (AML). Studies have shown that inhibitors of PI3K/AKT signaling, such as wortmannin and LY294002, are able to inhibit CML and AML cell proliferation and synergize with targeted tyrosine kinase inhi-bitors. We investigated the ability of BAG956, a dual PI3K/PDK-1 inhibitor, to be used in combination with inhibitors of BCR-ABL and mutant FLT3, as well as with the mTOR inhibitor, rapamycin, and the rapamycin derivative, RAD001. BAG956 was shown to block AKT phosphorylation induced by BCR-ABL–, and induce apoptosis of BCR-ABL–expressing cell lines and patient bone marrow cells at concentrations that also inhibit PI3K signaling. Enhancement of the inhibitory effects of the tyrosine kinase inhibitors, imatinib and nilotinib, by BAG956 was demonstrated against BCR-ABL expressing cells both in vitro and in vivo. We have also shown that BAG956 is effective against mutant FLT3-expressing cell lines and AML patient bone marrow cells. Enhancement of the inhibitory effects of the tyrosine kinase inhibitor, PKC412, by BAG956 was demonstrated against mutant FLT3-expressing cells. Finally, BAG956 and rapamycin/RAD001 were shown to combine in a nonantagonistic fashion against BCR-ABL– and mutant FLT3-expressing cells both in vitro and in vivo.
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Upadhayaya, Ram S., Raghava Reddy Kethiri, Avanish Vellanki, Jeff Lightfoot, Andrea Local e William G. Rice. "Discovery of Selective Dual Inhibitors of Bromodomain Protein BRD4 and JAK2 for Treatment of Hematologic Malignancies". Blood 128, n. 22 (2 dicembre 2016): 5212. http://dx.doi.org/10.1182/blood.v128.22.5212.5212.
Testo completoAbstract (sommario):
Abstract The Bromodomain and Extra-Terminal (BET) proteins (BRD2, BRD3, BRD4, and BRDT) are functional readers of acetylated lysine residues of histones, and have emerged as potential therapeutic targets in hematologic cancers and solid tumors characterized by dysregulated epigenetic processes. Targeted inhibition of BET proteins has proven to be an effective strategy for transcriptional downregulation of c-MYC, an oncogene that is frequently activated or overexpressed in leukemias, lymphomas, and multiple myeloma. Of the BET family members BRD4 is the most extensively studied for its role in cancer, furthermore C-MYC downregulation by BET inhibitors is attributed to inhibition of enhancer binding by BRD4 (Delmore et al., Cell. 2011. 146:904-17). BRD4 is a critical factor in AML disease maintenance (Zuber et al., Nature. 2011. 478:524-8), and its suppression is the dominant mechanism of BET inhibitor JQ1 activity in AML (Rathert et al., Nature. 2015. 525:543-7). Recent reports have shown that BRD4/BET inhibitors and kinase inhibitors act synergistically in a range of cancer types (Sun et al., Blood. 2015, 126:1565-74; Stratikopoulos et al., Cancer Cell. 2015, 27:837-51). Therefore, optimizing for this synergy by prospectively designing and developing multi-targeting BRD4-kinase inhibitors may prolong therapeutic efficacy and overcome tumor resistance of single-activity BET and oncogenic kinase inhibitors. Dual inhibitors of BET proteins and Janus kinase 2 (JAK2), initially developed by Moffitt Cancer Center (Reuther et al., ASH 2015 Poster, Abstract #2826), demonstrated an opportunity for novel, potent dual inhibitors of BRD4 and JAK for treatment of myeloproliferative neoplasms (MPNs) and other disorders driven by the constitutively active somatic mutation, JAK2-V617F. Although JAK inhibitors such as ruxolitinib show clinical benefits in MPNs, these molecules demonstrate limited ability to induce remissions and are associated with significant toxicities such as myelosuppression. Therefore, selective JAK2 inhibitors that also target BRD4 hold promise as treatments of hematologic malignancies with improved activity and less off-target toxicity. While the dual inhibitor candidates from Moffitt exhibit strong potency, they possess a sub-optimal profile for inhibition of the thiamine transporter and other properties. Herein, we report that next generation, novel dual inhibitors of BRD4 and JAK2 have been discovered by Aptose, in a collaboration with Laxai Avanti Life Sciences (LALS), without observed thiamine transporter inhibition but with favourable drug-like properties. In biochemical assays, the Aptose dual inhibitor compounds exhibit IC50 values ranging from 82-678 nM for BRD4 (BD1) and 0.7-35 nM for JAK2. Compounds exhibited selectivity of 2-7 fold for BRD4 compared to other BRD isoforms, and 3-152 fold selectivity for JAK2 over JAK1 or JAK3. Cellular IC50 values of the compounds in antiproliferative assays ranged from 6.6 - 118 nM in AML (MV4-11) and from 171-721 nM in myeloma (MM1.S) cell lines. Candidate structures show good solubility and metabolic stability in human, rat and mouse liver microsomes. Structure-activity relationship studies are ongoing to improve biochemical and antiproliferative activity and drug like properties. Collectively, we demonstrate that a rational design approach can be used to generate potent molecules with combined BRD4/JAK2 inhibitory activities for treatment of hematologic cancers. Disclosures No relevant conflicts of interest to declare.
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Wong, Jacky, Robert Welschinger, Rana Baraz, Jocelyn Weiss, Ken Bradstock e Linda J. Bendall. "Comparision of Dual PI-3K/mTOR Inhibitors with mTOR Inhibitors Using a Pre-Clinical Model of Acute Lymphoblastic Leukemia". Blood 116, n. 21 (19 novembre 2010): 3258. http://dx.doi.org/10.1182/blood.v116.21.3258.3258.
Testo completoAbstract (sommario):
Abstract Abstract 3258 ALL cells are highly dependent on bone marrow stromal support for in vitro proliferation and survival. The major regulators of patient-derived ALL cell growth and survival convey their proliferative and survival signals through the phosphoinositide 3-kinase (PI-3K) pathway. It has been recently demonstrated that signalling through PI-3K and AKT is the most important pathway for the proliferative responses of ALL cells to CXCL12, the chemokine predominantly responsible for stromal dependent growth of ALL cells. In addition, inhibition of the mTOR signalling molecule downstream of PI3K with RAD001 has been shown to inhibit proliferation and induce cell death. Although PI-3K and mTOR have similar and overlapping functions, mTOR can be activated independently of PI-3K, and proliferation and survival can be stimulated by PI-3K in an mTOR independent manner. Therefore combining PI-3K and mTOR inhibition is likely to be advantageous over inhibition of either kinase alone, suggesting disruption of PI-3K/AKT/mTOR signalling will provide a new approach for the treatment of ALL. We investigated the dual kinase inhibitors BEZ235 and BGT226. Here, we demonstrate that PI-3K and mTOR inhibition with the dual kinase inhibitor BEZ235 significantly inhibits ALL proliferation in vitro, with IC50 values in the range of 7–20nM, indicating a 3 log greater potency in comparison to the mTOR inhibitor RAD001. The ability to induce cell death differed between the dual mTOR and PI-3K inhibitors, with BGT226 potently inducing cell death at 1.6μM, but more than 16μM of BEZ235 was required to kill ALL cells, with a combination of autophagy and apoptosis being detected. While cell death was induced with higher concentrations of BEZ235 than needed to inhibit proliferation, clonogenic assays revealed a major decrease in the survival capacity of cells exposed to the agent. We also demonstrate the activity of these dual kinase inhibitors in a NOD/SCID xenograft model of human ALL with significantly prolonged survival of mice. The potential synergy of dual kinase inhibitors with conventional chemotherapy drugs and in mTOR inhibitor resistant cases remains to be studied. Dual kinase inhibitors may offer an improved therapeutic index through reduced toxicity over mTOR inhibitors, and potentially reduce the risk of development of resistance to kinase inhibition. Disclosures: No relevant conflicts of interest to declare.
22
Wong, Jacky, Robert Welschinger, Rana Baraz, Kenneth Francis Bradstock e Linda J. Bendall. "Application of Dual PI-3K/mTOR Inhibitors Is Not Always Superior to Inhibition of mTOR Alone.",. Blood 118, n. 21 (18 novembre 2011): 3575. http://dx.doi.org/10.1182/blood.v118.21.3575.3575.
Testo completoAbstract (sommario):
Abstract Abstract 3575 ALL cells are highly dependent on bone marrow stromal support for in vitro proliferation and survival. The major regulators of patient-derived ALL cell growth and survival convey their proliferative and survival signals through the phosphoinositide 3-kinase (PI-3K) pathway. It has been recently demonstrated that signalling through PI-3K and AKT is the most important pathway for the proliferative responses of ALL cells to CXCL12, the chemokine predominantly responsible for stromal dependent growth of ALL cells. In addition, inhibition of the mTOR signalling molecule downstream of PI-3K with RAD001 has been shown to inhibit proliferation and induce cell death resulting in extended survival in a NOD/SCID xenograft model of human ALL. This work has supported the initiation of clinical trials of RAD001 in adults with relapsed ALL. Although PI-3K and mTOR have similar and overlapping functions, mTOR can be activated independently of PI-3K, and proliferation and survival can be stimulated by PI-3K in an mTOR independent manner. Therefore combining PI-3K and mTOR inhibition is likely to be advantageous over inhibition of either kinase alone, suggesting disruption of PI-3K/AKT/mTOR signalling will provide a new approach for the treatment of ALL. We investigated the dual kinase inhibitors BEZ235 and BGT226. We have previously demonstrated that PI-3K and mTOR inhibition with the dual kinase inhibitor BEZ235 and BGT226 significantly inhibits the proliferation of ALL cell lines and patient derived stromal dependent lines in vitro, a 3 log greater potency in comparison to the mTOR inhibitor RAD001. The ability to induce cell death differed between the dual mTOR and PI-3K inhibitors. BGT226 potently induced cell death at 1.6μM, while more than 30μM of BEZ235 was required to kill ALL cells within 24 hours, compared to RAD001 which has an IC50 of 16μM. Interestingly, the IC50 for BEZ235 and BGT226 both declined when cell death was measured at 48 and 72 hours, a feature not observed with RAD001. BEZ235 induced extensive caspase 3 cleavage while BGT226 had only a minor effect on the activation of caspase 3. Preliminary data using 3H-thymidine assays, suggests that the addition of dual PI-3K/mTOR inhibitors may not be beneficial with antagonistic interactions being observed with some agents including etoposide and doxorubicin. Further studies will be required to define interactions between kinase inhibitors and chemotherapeutic agents. We also demonstrate the activity of these dual kinase inhibitors in a NOD/SCID xenograft model of human ALL, with treatment commencing once 1% ALL was detected in the blood. The dual kinase inhibitors significantly extended survival in all 4 xenografts compared to control treated animals. However they only produced superior results to RAD001 in one of these xenografts (2032) and were clearly inferior in another (1345). In xenograft 2023 exposure to RAD001 resulted in increased AKT phosphorylation on Ser473, suggesting RAD001 induced activation of mTORC2 through the mTORC1 feedback loop, potentially diminishing responses to mTOR inhibitors. This particularly highlights the benefit of the dual PI-3K/mTOR inhibitors' ability to block mTORC2 signalling through PI-3K inhibition and could possibly reflect the results seen with xenograft 2032 in vivo. The reason for reduced efficacy in xenograft 1345 is also not apparent at this stage but may possibly reflect greater bioavailability of RAD001 as compared to the dual kinase inhibitors. Interestingly, Akt signalling differed between xenografts, suggesting that dependence on PI-3K/Akt signalling upstream and potentially independent of mTOR may impact on the efficacy of the dual PI-3K/mTOR inhibitors however, this does not appear to provide a complete explanation of the different responses observed. Dual kinase inhibitors may offer improved therapeutic outcomes for a subset of ALL patients. More importantly some patients actually respond better to single mTOR inhibitors than dual inhibitors. We need a greater understanding of how these inhibitors work, so that patients that will benefit from dual kinase inhibitors and those where dual inhibitors will be less effective than single mTOR inhibitors can be identified prior to treatment. Disclosures: No relevant conflicts of interest to declare.
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Min, Jian, Jerome C. Nwachukwu, Charles K. Min, Jacqline W. Njeri, Sathish Srinivasan, Erumbi S. Rangarajan, Charles C. Nettles et al. "Dual-mechanism estrogen receptor inhibitors". Proceedings of the National Academy of Sciences 118, n. 35 (27 agosto 2021): e2101657118. http://dx.doi.org/10.1073/pnas.2101657118.
Testo completoAbstract (sommario):
Efforts to improve estrogen receptor-α (ER)–targeted therapies in breast cancer have relied upon a single mechanism, with ligands having a single side chain on the ligand core that extends outward to determine antagonism of breast cancer growth. Here, we describe inhibitors with two ER-targeting moieties, one of which uses an alternate structural mechanism to generate full antagonism, freeing the side chain to independently determine other critical properties of the ligands. By combining two molecular targeting approaches into a single ER ligand, we have generated antiestrogens that function through new mechanisms and structural paradigms to achieve antagonism. These dual-mechanism ER inhibitors (DMERIs) cause alternate, noncanonical structural perturbations of the receptor ligand-binding domain (LBD) to antagonize proliferation in ER-positive breast cancer cells and in allele-specific resistance models. Our structural analyses with DMERIs highlight marked differences from current standard-of-care, single-mechanism antiestrogens. These findings uncover an enhanced flexibility of the ER LBD through which it can access nonconsensus conformational modes in response to DMERI binding, broadly and effectively suppressing ER activity.
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van Gijn, R., R. R. H. Lendfers, J. H. M. Schellens, A. Bult e J. H. Beijnen. "Dual topoisomerase I/II inhibitors". Journal of Oncology Pharmacy Practice 6, n. 3 (1 marzo 2000): 92–108. http://dx.doi.org/10.1191/107815500701563317.
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25
Khan, Anwar A., e Guang-Wen Zeng. "Dual Action of Respiratory Inhibitors". Plant Physiology 77, n. 4 (1 aprile 1985): 817–23. http://dx.doi.org/10.1104/pp.77.4.817.
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van Gijn, R., RRH Lendfers, JHM Schellens, A. Bult e JH Beijnen. "Dual topoisomerase I/II inhibitors". Journal of Oncology Pharmacy Practice 6, n. 3 (settembre 2000): 92–108. http://dx.doi.org/10.1177/107815520000600303.
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Woo, L. W. Lawrence, Christian Bubert, Oliver B. Sutcliffe, Andrew Smith, Surinder K. Chander, Mary F. Mahon, Atul Purohit, Michael J. Reed e Barry V. L. Potter. "Dual Aromatase−Steroid Sulfatase Inhibitors". Journal of Medicinal Chemistry 50, n. 15 (luglio 2007): 3540–60. http://dx.doi.org/10.1021/jm061462b.
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Cai, Chao-Yun, Qiu-Xu Teng, Megumi Murakami, Suresh V. Ambudkar, Zhe-Sheng Chen e Vijaya L. Korlipara. "Design, Synthesis and Biological Evaluation of Quinazolinamine Derivatives as Breast Cancer Resistance Protein and P-Glycoprotein Inhibitors with Improved Metabolic Stability". Biomolecules 13, n. 2 (30 gennaio 2023): 253. http://dx.doi.org/10.3390/biom13020253.
Testo completoAbstract (sommario):
A series of twenty-two quinazolinamine derivatives showing potent inhibitory activities on breast cancer resistance protein (BCRP) and p-glycoprotein (P-gp) were synthesized. A cyclopropyl-containing quinazolinamine 22 was identified as a dual BCRP and P-gp inhibitor, while azide-containing quinazolinamine 33 showed BCRP inhibitory activity. These lead compounds were further investigated in a battery of mechanistic experiments. Compound 22 changed the localization of BCRP and P-gp in cells, thus inhibiting the efflux of anticancer drugs by the two ATP-binding cassette (ABC) transporters. In addition, both 22 and 33 significantly stimulated the ATP hydrolysis of the BCRP transporter, indicating that they can be competitive substrates of the BCRP transporter, and thereby increase the accumulation of mitoxantrone in BCRP-overexpressing H460/MX20 cells. Azide derivative 33, exhibited a greater inhibitory effect on BCRP after UV activation and can serve as a valuable probe for investigating the interactions of quinazolinamine derivatives with BCRP. Notably, the dual BCRP and P-gp inhibitors 4–5, 22–24, 27, and BCRP inhibitor 33 showed improved metabolic stability compared to Ko143.
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Kozak, Wieslaw, Inez Archuleta, Kimberly P. Mayfield, Anna Kozak, Karin Rudolph e Matthew J. Kluger. "Inhibitors of alternative pathways of arachidonate metabolism differentially affect fever in mice". American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 275, n. 4 (1 ottobre 1998): R1031—R1040. http://dx.doi.org/10.1152/ajpregu.1998.275.4.r1031.
Testo completoAbstract (sommario):
Inhibitors of cyclooxygenases prevent fever. The purpose of this study was to test the hypothesis that selective and dual inhibitors of the other enzyme systems of arachidonic acid oxygenation (i.e., lipoxygenase and epoxygenase) affect the time course or magnitude of fever in mice. Swiss Webster mice kept at 30°C ambient temperature were implanted with biotelemeters to monitor body temperature. Fever was induced by intraperitoneal injection of lipopolysaccharide at doses from 10 μg/kg to 2.5 mg/kg. Phenidone (20–30 mg/kg ip), a dual lipoxygenase and cyclooxygenase inhibitor, prevented fever in these mice, but esculetin (1–10 mg/kg ip), a selective inhibitor of lipoxygenases, did not affect fever. Intramuscular injection of nordihydroguaiaretic acid (10–20 mg/kg), a dual lipoxygenase and epoxygenase inhibitor, as well as SKF-525A (5 mg/kg ip) and clotrimazole (20 mg/kg im), inhibitors of the cytochrome P-450/epoxygenase pathway, augmented fever in mice. Indomethacin (5 mg/kg ip), an inhibitor of cyclooxygenase, suppressed the exacerbation of fever due to clotrimazole, suggesting that the epoxygenase inhibitor-induced potentiation of fever in mice is a prostaglandin-mediated effect. From this study, we hypothesize that the cytochrome P-450/epoxygenase branch of the arachidonate cascade is involved in antipyresis and in controlling the upper limit of fever.
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Kurup, Sonali, Gabe Carpenter, Samantha Satawa, Felix Amissah, Erika Lisabeth, Matthew Giletto e Edmund Ellsworth. "Abstract 4474: Novel analogs of 4-substituted pyrrolo[2,3-d]pyrimidines as dual-targeted mEGFR/AURKA inhibitors for lung cancer". Cancer Research 84, n. 6_Supplement (22 marzo 2024): 4474. http://dx.doi.org/10.1158/1538-7445.am2024-4474.
Testo completoAbstract (sommario):
Abstract Small molecule, mutant epidermal growth factor receptor kinase (mEGFR) inhibitors such as osimertinib and erlotinib constitute the recommended therapy for mEGFR-positive non-small cell lung cancer (NSCLC). However, mEGFR inhibitors are ineffective in NSCLC over time due to mutations within mEGFR and redundant signaling pathways such as mutant KRAS (mKRAS) that bypass mEGFR inhibition. Simultaneous inhibition of multiple kinases has been suggested to provide synergistic effects on tumor growth inhibition and tumor resistance. Studies have shown that resistance to mEGFR inhibitors was overcome when mEGFR inhibitors were combined with aurora kinase (AURK) inhibitors. Additionally, mEGFR inhibitors were found to retain their anticancer effects in mKRAS-positive NSCLC cells if given concurrently with AURK inhibitors. Kurup et al. previously reported a series of 4-substituted pyrrolo[2,3-d]pyrimidines as dual mEGFR/AURKB inhibitors. Novel analogs of 1-5 have been designed to incorporate AURKA inhibition while maintaining mEGFR inhibition. Molecular modeling was utilized to guide selectivity for AURKA over AURKB. This study led to the identification of novel dual-targeted mEGFR/AURKA inhibitors with demonstrated inhibition of mKRAS+ NSCLC and mEGFR+ NSCLC. The design, synthesis, kinase inhibitory activities, and anticancer effects for these novel analogs will be presented. Structure-activity relationships for dual mEGFR/AURKA inhibition will be defined. Citation Format: Sonali Kurup, Gabe Carpenter, Samantha Satawa, Felix Amissah, Erika Lisabeth, Matthew Giletto, Edmund Ellsworth. Novel analogs of 4-substituted pyrrolo[2,3-d]pyrimidines as dual-targeted mEGFR/AURKA inhibitors for lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4474.
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Wu, Yichao, Weichen Dai, Xin Chen, Aixin Geng, Yadong Chen, Tao Lu e Yong Zhu. "Design, synthesis and biological evaluation of 2,3-dihydroimidazo[1,2-c]quinazoline derivatives as novel phosphatidylinositol 3-kinase and histone deacetylase dual inhibitors". RSC Advances 7, n. 82 (2017): 52180–86. http://dx.doi.org/10.1039/c7ra08835c.
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Chen, Xin, Shuang Zhao, Yichao Wu, Yadong Chen, Tao Lu e Yong Zhu. "Design, synthesis and biological evaluation of 2-amino-N-(2-aminophenyl)thiazole-5-carboxamide derivatives as novel Bcr-Abl and histone deacetylase dual inhibitors". RSC Advances 6, n. 105 (2016): 103178–84. http://dx.doi.org/10.1039/c6ra21271a.
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Estrada, Filipe G. A., Silvia Miccoli, Natália Aniceto, Alfonso T. Garcia-Sosa e Rita C. Guedes. "Exploring EZH2-Proteasome Dual-Targeting Drug Discovery through a Computational Strategy to Fight Multiple Myeloma". Molecules 26, n. 18 (14 settembre 2021): 5574. http://dx.doi.org/10.3390/molecules26185574.
Testo completoAbstract (sommario):
Multiple myeloma is an incurable plasma cell neoplastic disease representing about 10–15% of all haematological malignancies diagnosed in developed countries. Proteasome is a key player in multiple myeloma and proteasome inhibitors are the current first-line of treatment. However, these are associated with limited clinical efficacy due to acquired resistance. One of the solutions to overcome this problem is a polypharmacology approach, namely combination therapy and multitargeting drugs. Several polypharmacology avenues are currently being explored. The simultaneous inhibition of EZH2 and Proteasome 20S remains to be investigated, despite the encouraging evidence of therapeutic synergy between the two. Therefore, we sought to bridge this gap by proposing a holistic in silico strategy to find new dual-target inhibitors. First, we assessed the characteristics of both pockets and compared the chemical space of EZH2 and Proteasome 20S inhibitors, to establish the feasibility of dual targeting. This was followed by molecular docking calculations performed on EZH2 and Proteasome 20S inhibitors from ChEMBL 25, from which we derived a predictive model to propose new EZH2 inhibitors among Proteasome 20S compounds, and vice versa, which yielded two dual-inhibitor hits. Complementarily, we built a machine learning QSAR model for each target but realised their application to our data is very limited as each dataset occupies a different region of chemical space. We finally proceeded with molecular dynamics simulations of the two docking hits against the two targets. Overall, we concluded that one of the hit compounds is particularly promising as a dual-inhibitor candidate exhibiting extensive hydrogen bonding with both targets. Furthermore, this work serves as a framework for how to rationally approach a dual-targeting drug discovery project, from the selection of the targets to the prediction of new hit compounds.
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Guenther, Andreas, Renate Burger, Wolfram Klapper, Matthias Staudinger, Kathrin Richter, Tanja Ahrens e Martin Gramatzki. "Inhibitors of Mtor and PI3K Synergistically Block Plasmacytoma Cell Growth". Blood 118, n. 21 (18 novembre 2011): 2903. http://dx.doi.org/10.1182/blood.v118.21.2903.2903.
Testo completoAbstract (sommario):
Abstract Abstract 2903 Introduction: Both, the phosphoinositide-3-kinase (PI3K)-AKT pathway as well as its nutrient-dependent downstream target, the mToR (mammalian target of rapamycin) kinase, are essential for the growth and survival of malignant plasma cells. PI3K-AKT can be activated by the loss of the tumor suppressor phosphatase and tensin homolog (PTEN) or by stimulation with cytokines such as interleukin-6 (IL-6) and insulin-like growth factor-1 (IGF-1). Inhibitors of the mToR pathway like sirolimus, everolimus and temsirolimus are approved for immunosuppression and treatment of renal cell cancer. In fact, they show activity in multiple myeloma patients. However, the clinical activity of mToR inhibitors may be limited by feedback loops in tumor cells that lead to activation of AKT upon inhibition of the rapamycin-sensitive Raptor complex. Selective PI3K inhibitors (Ly294002, NVP-BKM120) as well as dual PI3K-mToR inhibitors (NVP-BEZ235) are in clinical development. Here, the inhibitory effect of a panel of mToR and PI3K inhibitors, alone and in combination, was evaluated in malignant plasma cell lines and primary samples from myeloma patients. Results: In five human plasma cell lines, rapamycin, everolimus, Ly294002, NVP-BKM120 and NVP-BEZ235 (kindly provided by Novartis) induced a dose-dependent growth inhibition as measured by MTS assay. Despite the observed strong anti-myeloma activity of the mToR inhibitors rapamycin and everolimus with IC50 values in the nm range, the AKT pathway was activated as indicated by increased phosphorylation at Ser473. This observation was also made in explanted plasma cell tumors of INA-6 xenografted SCID mice that were treated with rapamycin, indicating that this feedback loop is also active in vivo. Therefore, combining mToR and PI3K inhibitors could be an effective strategy to overcome rapamycin-induced AKT activation. In fact, rapamycin in combination with the selective PI3K inhibitor Ly294002 or NVP-BKM120 led to synergistic growth inhibition in plasma cell lines, as calculated by the Calcusyn™ software (Biosoft). This abrogation of AKT activation was also seen in Western blot analysis. Combined treatment also enhanced the induction of apoptosis in cell lines as well as in plasmacytoma cells. Interestingly, the activity of the dual inhibitor NVP-BEZ235 could be even further enhanced by the addition of rapamycin. Conclusion: First clinical trials with mToR inhibitors showed anti-tumor activity and an acceptable safety profile in patients with multiple myeloma. The data presented here suggest that a combination of mToR inhibitors with PI3K targeting compounds or the use of dual inhibitors may have a favorable therapeutic potential. Disclosures: Guenther: Novartis, Celgene: Consultancy, Research Funding. Gramatzki:Novartis, Celgene: Consultancy, Research Funding.
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Kramer, Victor G., Susan M. Schader, Maureen Oliveira, Susan P. Colby-Germinario, Daniel A. Donahue, Diane N. Singhroy, Randy Tressler, Richard D. Sloan e Mark A. Wainberg. "Maraviroc and Other HIV-1 Entry Inhibitors Exhibit a Class-Specific Redistribution Effect That Results in Increased Extracellular Viral Load". Antimicrobial Agents and Chemotherapy 56, n. 8 (21 maggio 2012): 4154–60. http://dx.doi.org/10.1128/aac.00409-12.
Testo completoAbstract (sommario):
ABSTRACTHIV entry inhibitors, such as maraviroc (MVC), prevent cell-free viruses from entering the cells. In clinical trials, patients who were treated with MVC often displayed viral loads that were above the limit of conventional viral load detection compared to efavirenz-based regimens. We hypothesize that viruses blocked by entry inhibitors may be redistributed to plasma, where they artificially increase viral load measurements compared to those with the use of antiretroviral drugs (ARVs) that act intracellularly. We infected PM-1 cells with CCR5-tropic HIV-1 BaL or CXCR4-tropic HIV-1 NL4-3 in the presence of inhibitory concentrations of efavirenz, raltegravir, enfuvirtide, maraviroc, and AMD3100, the latter three being entry inhibitors. Supernatant viral load, reverse transcriptase enzyme activity, and intracellular nucleic acid levels were measured at times up to 24 h postinfection. Infectivity of redistributed dual-tropic HIV-1 was assessed using TZM-bl cells. Extracellular viral load analysis revealed that entry inhibitor-treated cells had higher levels of virus in the supernatant than the cells treated with other ARVs at 8 h postinfection. By 24 h, the supernatant viral load was still higher for entry inhibitors than other ARVs. We observed a correlation between viral load and the step of entry inhibition. Dual-tropic virus infectivity was undiminished utilizing the CCR5 coreceptor following redistribution by CXCR4 entry inhibition. Thisin vitromodel indicates that entry inhibitors exhibit a redistribution effect unseen with intracellular ARV drugs. Based on these results, the effectiveness of some entry inhibitors may be underestimated if plasma viral load is used as a sole indicator of clinical success.
36
Leufven, Eva, e Øystein Bruserud. "Immunosuppression and Immunotargeted Therapy in Acute Myeloid Leukemia - The Potential Use of Checkpoint Inhibitors in Combination with Other Treatments". Current Medicinal Chemistry 26, n. 28 (25 ottobre 2019): 5244–61. http://dx.doi.org/10.2174/0929867326666190325095853.
Testo completoAbstract (sommario):
Introduction: Immunotherapy by using checkpoint inhibitors is now tried in the treatment of several malignancies, including Acute Myeloid Leukemia (AML). The treatment is tried both as monotherapy and as a part of combined therapy. Methods: Relevant publications were identified through literature searches in the PubMed database. We searched for (i) original articles describing the results from clinical studies of checkpoint inhibition; (ii) published articles describing the immunocompromised status of AML patients; and (iii) published studies of antileukemic immune reactivity and immunotherapy in AML. Results: Studies of monotherapy suggest that checkpoint inhibition has a modest antileukemic effect and complete hematological remissions are uncommon, whereas combination with conventional chemotherapy increases the antileukemic efficiency with acceptable toxicity. The experience with a combination of different checkpoint inhibitors is limited. Thalidomide derivatives are referred to as immunomodulatory drugs and seem to reverse leukemia-induced immunosuppression, but in addition, they have direct inhibitory effects on the AML cells. The combination of checkpoint targeting and thalidomide derivatives thus represents a strategy for dual immunotargeting together with a direct antileukemic effect. Conclusion: Checkpoint inhibitors are now tried in AML. Experimental studies suggest that these inhibitors should be combined with immunomodulatory agents (i.e. thalidomide derivatives) and/or new targeted or conventional antileukemic treatment. Such combinations would allow dual immunotargeting (checkpoint inhibitor, immunomodulatory agents) together with a double/triple direct targeting of the leukemic cells.
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Bao, Le-Quang, Daniel Baecker, Do Thi Mai Dung, Nguyen Phuong Nhung, Nguyen Thi Thuan, Phuong Linh Nguyen, Phan Thi Phuong Dung et al. "Development of Activity Rules and Chemical Fragment Design for In Silico Discovery of AChE and BACE1 Dual Inhibitors against Alzheimer’s Disease". Molecules 28, n. 8 (20 aprile 2023): 3588. http://dx.doi.org/10.3390/molecules28083588.
Testo completoAbstract (sommario):
Multi-target drug development has become an attractive strategy in the discovery of drugs to treat of Alzheimer’s disease (AzD). In this study, for the first time, a rule-based machine learning (ML) approach with classification trees (CT) was applied for the rational design of novel dual-target acetylcholinesterase (AChE) and β-site amyloid-protein precursor cleaving enzyme 1 (BACE1) inhibitors. Updated data from 3524 compounds with AChE and BACE1 measurements were curated from the ChEMBL database. The best global accuracies of training/external validation for AChE and BACE1 were 0.85/0.80 and 0.83/0.81, respectively. The rules were then applied to screen dual inhibitors from the original databases. Based on the best rules obtained from each classification tree, a set of potential AChE and BACE1 inhibitors were identified, and active fragments were extracted using Murcko-type decomposition analysis. More than 250 novel inhibitors were designed in silico based on active fragments and predicted AChE and BACE1 inhibitory activity using consensus QSAR models and docking validations. The rule-based and ML approach applied in this study may be useful for the in silico design and screening of new AChE and BACE1 dual inhibitors against AzD.
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Spinaci, Andrea, Michela Buccioni, Daniela Catarzi, Chang Cui, Vittoria Colotta, Diego Dal Ben, Eleonora Cescon et al. "“Dual Anta-Inhibitors” of the A2A Adenosine Receptor and Casein Kinase CK1delta: Synthesis, Biological Evaluation, and Molecular Modeling Studies". Pharmaceuticals 16, n. 2 (23 gennaio 2023): 167. http://dx.doi.org/10.3390/ph16020167.
Testo completoAbstract (sommario):
Based on a screening of a chemical library of A2A adenosine receptor (AR) antagonists, a series of di- and tri-substituted adenine derivatives were synthesized and tested for their ability to inhibit the activity of the enzyme casein kinase 1 delta (CK1δ) and to bind adenosine receptors (ARs). Some derivatives, here called “dual anta-inhibitors”, demonstrated good CK1δ inhibitory activity combined with a high binding affinity, especially for the A2AAR. The N6-methyl-(2-benzimidazolyl)-2-dimethyamino-9-cyclopentyladenine (17, IC50 = 0.59 μM and KiA2A = 0.076 μM) showed the best balance of A2AAR affinity and CK1δ inhibitory activity. Computational studies were performed to simulate, at the molecular level, the protein–ligand interactions involving the compounds of our series. Hence, the dual anta-inhibitor 17 could be considered the lead compound of new therapeutic agents endowed with synergistic effects for the treatment of chronic neurodegenerative and cancer diseases.
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Zhang, Lingzhi, Qiurong Ju, Jinjin Sun, Lei Huang, Shiqi Wu, Shuping Wang, Yin Li, Zhe Guan, Qihua Zhu e Yungen Xu. "Discovery of Novel Dual Extracellular Regulated Protein Kinases (ERK) and Phosphoinositide 3-Kinase (PI3K) Inhibitors as a Promising Strategy for Cancer Therapy". Molecules 25, n. 23 (3 dicembre 2020): 5693. http://dx.doi.org/10.3390/molecules25235693.
Testo completoAbstract (sommario):
Concomitant inhibition of MAPK and PI3K signaling pathways has been recognized as a promising strategy for cancer therapy, which effectively overcomes the drug resistance of MAPK signaling pathway-related inhibitors. Herein, we report the scaffold-hopping generation of a series of 1H-pyrazolo[3,4-d]pyrimidine dual ERK/PI3K inhibitors. Compound 32d was the most promising candidate, with potent inhibitory activities against both ERK2 and PI3Kα which displays superior anti-proliferative profiles against HCT116 and HEC1B cancer cells. Meanwhile, compound 32d possessed acceptable pharmacokinetic profiles and showed more efficacious anti-tumor activity than GDDC-0980 and the corresponding drug combination (BVD-523 + GDDC-0980) in HCT-116 xenograft model, with a tumor growth inhibitory rate of 51% without causing observable toxic effects. All the results indicated that 32d was a highly effective anticancer compound and provided a promising basis for further optimization towards dual ERK/PI3K inhibitors.
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Bachmann, Luisa M., Maria Hanl, Felix Feller, Laura Sinatra, Andrea Schöler, Jens Pietzsch, Markus Laube e Finn K. Hansen. "Solid-Phase Parallel Synthesis of Dual Histone Deacetylase-Cyclooxygenase Inhibitors". Molecules 28, n. 3 (20 gennaio 2023): 1061. http://dx.doi.org/10.3390/molecules28031061.
Testo completoAbstract (sommario):
Multi-target drugs (MTDs) are emerging alternatives to combination therapies. Since both histone deacetylases (HDACs) and cyclooxygenase-2 (COX-2) are known to be overexpressed in several cancer types, we herein report the design, synthesis, and biological evaluation of a library of dual HDAC-COX inhibitors. The designed compounds were synthesized via an efficient parallel synthesis approach using preloaded solid-phase resins. Biological in vitro assays demonstrated that several of the synthesized compounds possess pronounced inhibitory activities against HDAC and COX isoforms. The membrane permeability and inhibition of cellular HDAC activity of selected compounds were confirmed by whole-cell HDAC inhibition assays and immunoblot experiments. The most promising dual inhibitors, C3 and C4, evoked antiproliferative effects in the low micromolar concentration range and caused a significant increase in apoptotic cells. In contrast to previous reports, the simultaneous inhibition of HDAC and COX activity by dual HDAC-COX inhibitors or combination treatments with vorinostat and celecoxib did not result in additive or synergistic anticancer activities.
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Ţînţaş, Mihaela-Liliana, Ludovic Peauger, Florent Alix, Cyril Papamicaël, Thierry Besson, Jana Sopková-de Oliveira Sopková-de Oliveira Santos, Vincent Gembus e Vincent Levacher. "Straightforward Access to a New Class of Dual DYRK1A/CLK1 Inhibitors Possessing a Simple Dihydroquinoline Core". Molecules 28, n. 1 (21 dicembre 2022): 36. http://dx.doi.org/10.3390/molecules28010036.
Testo completoAbstract (sommario):
The DYRK (Dual-specificity tyrosine phosphorylation-regulated kinase) family of protein kinases is involved in the pathogenesis of several neurodegenerative diseases. Among them, the DYRK1A protein kinase is thought to be implicated in Alzheimer’s disease (AD) and Down syndrome, and as such, has emerged as an appealing therapeutic target. DYRKs are a subset of the CMGC (CDK, MAPKK, GSK3 and CLK) group of kinases. Within this group of kinases, the CDC2-like kinases (CLKs), such as CLK1, are closely related to DYRKs and have also sparked great interest as potential therapeutic targets for AD. Based on inhibitors previously described in the literature (namely TG003 and INDY), we report in this work a new class of dihydroquinolines exhibiting inhibitory activities in the nanomolar range on hDYRK1A and hCLK1. Moreover, there is overwhelming evidence that oxidative stress plays an important role in AD. Pleasingly, the most potent dual kinase inhibitor 1p exhibited antioxidant and radical scavenging properties. Finally, drug-likeness and molecular docking studies of this new class of DYRK1A/CLK1 inhibitors are also discussed in this article.
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Molins, Joaquim Bellmunt, Lillian Werner, Marta Guix, Elizabeth Ann Guancial, Fabio Augusto Barros Schutz, Robert O'Brien, Edward C. Stack et al. "PI3KCA mutations in advanced urothelial carcinoma: A potential therapeutic target?" Journal of Clinical Oncology 30, n. 15_suppl (20 maggio 2012): 4582. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.4582.
Testo completoAbstract (sommario):
4582 Background: PI3KCA is frequently mutated in human cancer; however, information is scarce regarding its relevance in urothelial carcinoma (UC). We determined the prevalence of mutation and impact on clinical outcome of PI3KCA uniformly-treated patients with metastatic UC. Impact of PI3K and dual PI3K/mTOR inhibition was tested in vitro in UC cell lines with either H1047R or E545K mutation. Methods: 141 samples from invasive UC were scanned for mutations. Of those, complete clinical data was available from 85 cases treated with platinum-based combination chemotherapy for advanced or metastatic disease. DNA was extracted from FFPE material. Mutation status was determined by iPLEX sequencing and confirmed with hME sequencing. Overall survival (OS) was measured from beginning of treatment for metastatic disease to time of death or censored on the last known alive date. Cox proportional hazard model was used to assess the associations of PI3K mutational status and OS. Growth inhibitory effects of a specific PI3K inhibitor and a dual PI3K/mTOR inhibitor (both from Selleck) on UC cell lines with or without mutations were tested using MTT assays. Results: Mutations in the PI3KCA gene were observed in 14 (10%; 95% CI 6-16%) specimens. E545K was detected in all 14 specimens, though one specimen contained mutation at both E545K and H1047R. Among patients with clinical data, there was no statistically significant association between PI3KCA mutational status and OS (HR for having PI3KCA=0.49, 95% CI [0.15, 1.57], p-value 0.22). Preliminary in vitro experiments showed that cell growth was more potently inhibited with dual PI3K/mTOR inhibitors than with PI3K inhibitors. Conclusions: Mutations in the PI3KCA gene were detected in 10% of invasive UC and did not correlate with OS in patients with metastatic UC treated with platinum-based chemotherapy. PI3K inhibition in vitro impacts UC cell growth, though dual PI3K/mTOR inhibitors may have more significant effects than PI3K inhibition alone.
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Woo, L. W. Lawrence, Christian Bubert, Atul Purohit e Barry V. L. Potter. "Hybrid Dual Aromatase-Steroid Sulfatase Inhibitors with Exquisite Picomolar Inhibitory Activity". ACS Medicinal Chemistry Letters 2, n. 3 (29 dicembre 2010): 243–47. http://dx.doi.org/10.1021/ml100273k.
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Jończyk, Jakub, Justyna Godyń, Ewelina Stawarska, Beata Morak-Młodawska, Małgorzata Jeleń, Krystian Pluta e Barbara Malawska. "Dual Action of Dipyridothiazine and Quinobenzothiazine Derivatives—Anticancer and Cholinesterase-Inhibiting Activity". Molecules 25, n. 11 (3 giugno 2020): 2604. http://dx.doi.org/10.3390/molecules25112604.
Testo completoAbstract (sommario):
The inverse correlation observed between Alzheimer’s disease (AD) and cancer has prompted us to look for cholinesterase-inhibiting activity in phenothiazine derivatives that possess anticancer properties. With the use of in silico and in vitro screening methods, our study found a new biological activity in anticancer polycyclic, tricyclic, and tetracyclic compounds. The virtual screening of a library of 120 ligands, which are the derivatives of azaphenothiazine, led to the identification of 25 compounds that can act as potential inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Biological assays revealed the presence of selective inhibitors of eeAChE (electric eel AChE) or eqBuChE (equine serum BuChE) and nonselective inhibitors of both enzymes among the tested compounds. Their potencies against eeAChE were in a submicromolar-to-micromolar range with IC50 values from 0.78 to 19.32 μM, while their IC50 values against eqBuChE ranged from 0.46 to 10.38 μM. The most potent among the compounds tested was the tetracyclic derivative, 6-(4-diethylaminobut-2-ynyl)-9-methylthioquinobenzothiazine 24, which was capable of inhibiting both enzymes. 9-Fluoro-6-(1-piperidylethyl)quinobenzothiazine 23 was found to act as a selective inhibitor of eqBuChE with an IC50 value of 0.46 μM. Compounds with such a dual antitumor and cholinesterase-inhibitory activity can be considered as a valuable combination for the treatment of both cancer and AD prevention. The results presented in this study might open new directions of research on the group of tricyclic phenothiazine derivatives.
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Mahnashi, Mater H., Sravanthi Avunoori, Sanjay Gopi, Ibrahim Ahmed Shaikh, Ahmed Saif, Farkad Bantun, Hani Saleh Faidah et al. "Synthesis, molecular docking study and biological evaluation of new pyrrole scaffolds as potential antitubercular agents for dual targeting of enoyl ACP reductase and dihydrofolate reductase". PLOS ONE 19, n. 5 (13 maggio 2024): e0303173. http://dx.doi.org/10.1371/journal.pone.0303173.
Testo completoAbstract (sommario):
In this study, new series of N’-(2-(substitutedphenoxy)acetyl)-4-(1H-pyrrol-1-yl)benzohydrazides (3a-j) 4-(2,5-dimethyl-1H-pyrrol-1-yl)-N’-(2-(substitutedphenoxy)acetyl)benzohydrazides (5a-j) were synthesized, characterized and assessed as inhibitors of enoyl ACP reductase and DHFR. Most of the compounds exhibited dual inhibition against the enzymes enoyl ACP reductase and DHFR. Several synthesized substances also demonstrated significant antibacterial and antitubercular properties. A molecular docking analysis was conducted in order to determine the potential mechanism of action of the synthesized compounds. The results indicated that there were binding interactions seen with the active sites of dihydrofolate reductase and enoyl ACP reductase. Additionally, important structural details were identified that play a critical role in sustaining the dual inhibitory activity. These findings were useful for the development of future dual inhibitors. Therefore, this study provided strong evidence that several synthesized molecules could exert their antitubercular properties at the cellular level through multi-target inhibition. By shedding light on the mechanisms through which these compounds exert their inhibitory effects, this research opens up promising avenues for the future development of dual inhibitors with enhanced antibacterial and antitubercular properties. The study’s findings underscore the importance of multi-target approaches in drug design, providing a strong foundation for the design and optimization of novel compounds that can effectively target bacterial infections at the cellular level.
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Kwon, Young-Ju, Dong Young Kim, Uk-Il Kim, Xue Meng, Ho Kyun Lee, Hyung Tae Bang, Jae-Sung Kim e Kyungjin Kim. "Abstract 491: Tankyrase-selective inhibitor STP1002 reverses resistance to MEK inhibitors in colorectal cancer with KRAS mutations". Cancer Research 83, n. 7_Supplement (4 aprile 2023): 491. http://dx.doi.org/10.1158/1538-7445.am2023-491.
Testo completoAbstract (sommario):
Abstract Mitogen-activated protein kinase (MEK) inhibitors have shown promising results in KRAS-mutated cancers with constitutive activation of the RAS/RAF/MEK pathway. However, the intrinsic and acquired resistance to MEK inhibitors is frequently observed in clinical trials. Wnt/β-catenin signaling hyper-activation is reported to be responsible for such resistance in colorectal cancer (CRC). Herein, we introduce a novel tankyrase inhibitor STP1002 to revert the intrinsic and acquired resistance to MEK inhibitors in KRAS-mutated CRC. Dual combination of STP1002 and MEK inhibitor synergistically reduced the oncogenic activity of KRAS (G12V or G12D)-mutated CRC cell lines. Data also showed that concomitant treatment with STP1002 and MEK inhibitor dramatically inhibited tumor growth of KRAS (G12V)-mutated CRC xenograft animal models. Moreover, the combination treatment sensitized the acquired MEK inhibitor-resistant CRC cells and suppressed the Wnt/YAP pathway which is the bypass mechanism of MEK inhibitor resistance. Dual combination of STP1002 and MEK inhibitor is a promising candidate to overcome resistance to MEK inhibitors in colorectal cancer with KRAS-G12V/G12D mutations. The phase 1 clinical trial study is ongoing in order to show safety margin. Citation Format: Young-Ju Kwon, Dong Young Kim, Uk-Il Kim, Xue Meng, Ho Kyun Lee, Hyung Tae Bang, Jae-Sung Kim, Kyungjin Kim. Tankyrase-selective inhibitor STP1002 reverses resistance to MEK inhibitors in colorectal cancer with KRAS mutations [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 491.
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Al-Wahaibi, Lamya H., Hesham A. Abou-Zied, Mohamed Hisham, Eman A. M. Beshr, Bahaa G. M. Youssif, Stefan Bräse, Alaa M. Hayallah e Mohamed Abdel-Aziz. "Design, Synthesis, and Biological Evaluation of Novel 3-Cyanopyridone/Pyrazoline Hybrids as Potential Apoptotic Antiproliferative Agents Targeting EGFR/BRAFV600E Inhibitory Pathways". Molecules 28, n. 18 (12 settembre 2023): 6586. http://dx.doi.org/10.3390/molecules28186586.
Testo completoAbstract (sommario):
A series of novel 3-cyanopyridone/pyrazoline hybrids (21–30) exhibiting dual inhibition against EGFR and BRAFV600E has been developed. The synthesized target compounds were tested in vitro against four cancer cell lines. Compounds 28 and 30 demonstrated remarkable antiproliferative activity, boasting GI50 values of 27 nM and 25 nM, respectively. These hybrids exhibited dual inhibitory effects on both EGFR and BRAFV600E pathways. Compounds 28 and 30, akin to Erlotinib, displayed promising anticancer potential. Compound 30 emerged as the most potent inhibitor against cancer cell proliferation and BRAFV600E. Notably, both compounds 28 and 30 induced apoptosis by elevating levels of caspase-3 and -8 and Bax, while downregulating the antiapoptotic Bcl2 protein. Molecular docking studies confirmed the potential of compounds 28 and 30 to act as dual EGFR/BRAFV600E inhibitors. Furthermore, in silico ADMET prediction indicated that most synthesized 3-cyanopyridone/pyrazoline hybrids exhibit low toxicity and minimal adverse effects.
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Tanabe, Kenji. "Microtubule Depolymerization by Kinase Inhibitors: Unexpected Findings of Dual Inhibitors". International Journal of Molecular Sciences 18, n. 12 (23 novembre 2017): 2508. http://dx.doi.org/10.3390/ijms18122508.
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Tabrizchi, Reza. "Dual ACE and Neutral Endopeptidase Inhibitors". Drugs 63, n. 20 (2003): 2185–202. http://dx.doi.org/10.2165/00003495-200363200-00003.
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Omidkhah, Negar, Farzin Hadizadeh e Razieh Ghodsi. "Dual HDAC/BRD4 inhibitors against cancer". Medicinal Chemistry Research 30, n. 10 (14 agosto 2021): 1822–36. http://dx.doi.org/10.1007/s00044-021-02776-9.
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