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1
Diacovo, Thomas, Dosh Whye, Evgeni Efimenko, Jianchung Chen, Valeria Tosello, Kim De Keersmaecker, Adam Kashishian, et al. "Therapeutic Utility of PI3Kγ Inhibition in Leukemogenesis and Tumor Cell Survival." Blood 120, no. 21 (November 16, 2012): 1492. http://dx.doi.org/10.1182/blood.v120.21.1492.1492.
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Abstract Abstract 1492 Aberrant activation of the PI3K/Akt signaling pathway is a frequent event in cancer including various types of leukemia. Consequently, much emphasis has been placed on developing inhibitors that target this pathway. However, this would require an in depth knowledge of the role that specific class I PI3K isoforms (α, β, γ, δ)play in the pathogenesis of a particular hematological malignancy. For instance, PI3Kδ has been shown to be essential for the growth and survival of tumors derived from B cells such as chronic lymphocytic leukemia (CLL). Such knowledge has lead to development of the selective inhibitor GS-1101 (CAL-101) that has shown significant efficacy in clinical trials. Although PI3Kγ plays an important role in modulating the immune function of T cells, its role in leukemogenesis and tumor cell survival is poorly defined. Thus, it is unclear whether an inhibitor that also targets PI3Kγ would be of any benefit in hematological malignancies. T cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer resulting from clonal proliferation of T lymphoid precursors. Previous reports suggest that hyperactivation of the PI3K/Akt signaling pathway is a common feature of this disease with the majority of cases due to the loss of function of the tumor suppressor PTEN. However, it remains to be determined whether any particular class I PI3K isoform predominates in T-ALL pathogenesis. We now report that in the absence of PTEN-mediated regulation in T cell progenitors that PI3Kγ can promote leukemogenesis even in the absence of its delta counterpart. However, inactivation of both isoforms was necessary for the suppression of tumor development in animals (< 20% dead at 220 days as compare to >85% for controls), suggesting that PI3Kα and/or PI3Kβ cannot adequately compensate for a deficiency in their γ/δ counterparts. The importance of PI3Kγ in tumor progression was established by the inability of the PI3Kδ selective inhibitor IC87114 to reduce tumor burden in mice (Fig. 1A). In contrast, treatment of PI3Kγ deficient tumors with the same inhibitor dramatically reduced disease in affected tissues (Fig. 1B). Based on these observations we developed an inhibitor, designated CAL-130, which targets both PI3Kγ and PI3Kδ in an attempt to exploit the addiction of PTEN null T-ALL tumors to both isoforms. IC50 values of this compound were 1.3 nM and 6.1 nM for p110δ and p110γ catalytic domains, respectively, as compared to 115 nM and 56 nM for p110α and p110β. Importantly, this small molecule does not inhibit additional intracellular signaling pathways (>300 kinases tested) that are critical for general cell function and survival. Oral administration of this compound to diseased mice (blast counts > 50 million/ml) for 7 days reduced tumor burden and extended median survival of treated animals to 45 day as compared 7.5 days for the control group (P<0.001). Of note, this inhibitor did not perturb plasma insulin or glucose levels in contrast to the metabolic perturbations associated with tissue-specific deficiencies in PI3Kα and PI3Kβ. The efficacy of this dual inhibitor was not limited to murine tumors as dual inhibition of PI3Kγ and PI3Kδ in primary human T-ALL cells displaying hyperactivation of this signaling pathway also reduced tumor cell survival by promoting activation of pro-apoptotic pathways. This work advances our understanding of the role that distinct PI3K isoforms play in development and survival of T-ALL and suggest that it may be possible to therapeutically exploit the addiction of this hematological malignancy to PI3Kγ and PI3Kδ. Moreover, by selectively targeting a signaling pathway key to tumor survival, it may be possible to limit toxicities associated with conventional chemotherapeutic agents that broadly affect metabolic pathways and DNA replication. Current studies are focused on evaluating the synergistic effect of PI3Kγ/δ blockade in combination with conventional chemotherapeutic agents used in the treatment of T-ALL. Disclosures: Kashishian: Gilead Sciences: Employment. Lannutti:Gilead Sciences Inc: Employment.
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Borsari, Chiara, and Matthias P. Wymann. "Targeting Phosphoinositide 3-Kinase – Five Decades of Chemical Space Exploration." CHIMIA 75, no. 12 (December 9, 2021): 1037. http://dx.doi.org/10.2533/chimia.2021.1037.
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Phosphoinositide 3-kinase (PI3K) takes a key role in a plethora of physiologic processes and controls cell growth, metabolism, immunity, cardiovascular and neurological function, and more. The discovery of wortmannin as the first potent PI3K inhibitor (PI3Ki) in the 1990s provided rapid identification of PI3K-dependent processes, which drove the assembly of the PI3K/protein kinase B (PKB/Akt)/target of rapamycin (mTOR) pathway. Genetic mouse models and first PI3K isoform-specific inhibitors pinpointed putative therapeutic applications. The recognition of PI3K as target for cancer therapy drove subsequently drug development. Here we provide a brief journey through the emerging roles of PI3K to the development of clinical PI3Ki candidates.
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Barberis, Laura, and Emilio Hirsch. "Targeting phosphoinositide 3-kinase γ to fight inflammation and more." Thrombosis and Haemostasis 99, no. 02 (2008): 279–85. http://dx.doi.org/10.1160/th07-10-0632.
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SummaryThe family of class I phosphoinositide-3-kinase (PI3K) is composed of four lipid kinases involved at multiple levels in innate and adaptive immune responses. Class I PI3Ks are divided into two subclasses, IA and IB, sharing a similar catalytic core. Whereas class IA PI3Ks are primarily activated by receptor tyrosine kinases, the unique element of class IB PI3K (PI3Kγ) is activated by G protein coupled receptors (GPCRs), like chemokine receptors. PI3Kγ is mainly expressed in leukocytes where it plays a significant role in chemotaxis. Here, we report recent advances in the analysis of the role of PI3Kγ in leukocytes and in endothelial cells. Results, derived from studies based on both pharmacological and genetic approaches, confirm PI3Kγ as an attractive target for drug discovery. PI3Kγ specific inhibition has gained increasing attention for the treatment of allergic, autoimmune and inflammatory diseases. Development of inhibitors has already provided series of hits, whose efficacy is currently under scrutiny worldwide.
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Miller, Michelle, Philip Thompson, and Sandra Gabelli. "Structural Determinants of Isoform Selectivity in PI3K Inhibitors." Biomolecules 9, no. 3 (February 26, 2019): 82. http://dx.doi.org/10.3390/biom9030082.
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Phosphatidylinositol 3-kinases (PI3Ks) are important therapeutic targets for the treatment of cancer, thrombosis, and inflammatory and immune diseases. The four highly homologous Class I isoforms, PI3Kα, PI3Kβ, PI3Kγ and PI3Kδ have unique, non-redundant physiological roles and as such, isoform selectivity has been a key consideration driving inhibitor design and development. In this review, we discuss the structural biology of PI3Ks and how our growing knowledge of structure has influenced the medicinal chemistry of PI3K inhibitors. We present an analysis of the available structure-selectivity-activity relationship data to highlight key insights into how the various regions of the PI3K binding site influence isoform selectivity. The picture that emerges is one that is far from simple and emphasizes the complex nature of protein-inhibitor binding, involving protein flexibility, energetics, water networks and interactions with non-conserved residues.
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Mercurio, Laura, Martina Morelli, Claudia Scarponi, Giovanni Luca Scaglione, Sabatino Pallotta, Cristina Albanesi, and Stefania Madonna. "PI3Kδ Sustains Keratinocyte Hyperproliferation and Epithelial Inflammation: Implications for a Topically Druggable Target in Psoriasis." Cells 10, no. 10 (October 2, 2021): 2636. http://dx.doi.org/10.3390/cells10102636.
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The phosphatidylinositol 3-kinase (PI3K)-dependent signaling pathway is aberrantly activated in psoriatic lesions and contributes to disease pathogenesis. Among PI3Ks enzymes, PI3Kα, β, and δ isoforms are known to bind the p85 regulatory subunit and mediate activation of AKT and other downstream effectors. In this study, we deepened our understanding of the expression and function of PI3Kδ in skin lesions of patients affected by psoriasis. For the first time, we found that PI3Kδ is overexpressed in psoriatic plaques, and its expression is not only confined to infiltrating immune cells but also accumulates in proliferating keratinocytes of the epidermal basal layer. We investigated the function of PI3Kδ in psoriatic skin by evaluating the impact of seletalisib, a newly developed selective PI3Kδ inhibitor, in both in vitro and in vivo experimental models of psoriasis. Of note, we found that PI3Kδ sustains keratinocyte hyperproliferation and impaired terminal differentiation induced by IL-22, as well as induces epithelial inflammation and resistance to apoptosis mediated by TNF-α in human keratinocytes. Mechanistically, PI3Kδ promotes PDK1 phosphorylation and signals through AKT-dependent or -independent pathways. It is worth mentioning that PI3Kδ inhibition by seletalisib attenuates the severity of psoriasiform phenotype induced in the Imiquimod-induced mouse model of psoriasis by restoring the physiological proliferation and differentiation programs in epidermal keratinocytes and contrasting the cutaneous inflammatory responses. Therefore, we suggest PI3Kδ as a potential topically druggable target in psoriasis and skin diseases characterized by epidermal hyperproliferation and skin inflammation.
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Laurent, Pierre-Alexandre, Cédric Garcia, Marie-Pierre Gratacap, Bart Vanhaesebroeck, Pierre Sié, Bernard Payrastre, and Anne-Dominique Terrisse. "The class I phosphoinositide 3-kinases α and β control antiphospholipid antibodies-induced platelet activation." Thrombosis and Haemostasis 115, no. 06 (2016): 1138–46. http://dx.doi.org/10.1160/th15-08-0661.
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SummaryAntiphospholipid syndrome (APS) is an autoimmune disease characterised by the presence of antiphospholipid antibodies (aPL) associated with increased thrombotic risk and pregnancy morbidity. Although aPL are heterogeneous auto-antibodies, the major pathogenic target is the plasma protein β2-glycoprotein 1. The molecular mechanisms of platelet activation by aPL remain poorly understood. Here, we explored the role of the class IA phosphoinositide 3-kinase (PI3K) α and β isoforms in platelet activation by aPL. Compared to control IgG from healthy individuals, the IgG fraction isolated from patients with APS potentiates platelet aggregation induced by low dose of thrombin in vitro and increases platelet adhesion and thrombus growth on a collagen matrix under arterial shear rate through a mechanism involving glycoprotein Ib (GPIb) and Toll Like Receptor 2 (TLR-2). Using isoforms-selective pharmacological PI3K inhibitors and mice with megakaryocyte/platelet lineage-specific inactivation of class IA PI3K isoforms, we demonstrate a critical role of the PI3Kβ and PI3Kα isoforms in platelet activation induced by aPL. Our data show that aPL potentiate platelet activation through GPIbα and TLR-2 via a mechanism involving the class IA PI3Kα and β isoforms, which represent new potential therapeutic targets in the prevention or treatment of thrombotic events in patients with APS.
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Kuracha, Murali R., Venkatesh Govindarajan, Brian W. Loggie, Martin Tobi, and Benita L. McVicker. "Pictilisib-Induced Resistance Is Mediated through FOXO1-Dependent Activation of Receptor Tyrosine Kinases in Mucinous Colorectal Adenocarcinoma Cells." International Journal of Molecular Sciences 24, no. 15 (August 2, 2023): 12331. http://dx.doi.org/10.3390/ijms241512331.
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The phosphatidylinositol (PI3K)/AKT/mTOR axis represents an important therapeutic target to treat human cancers. A well-described downstream target of the PI3K pathway is the forkhead box O (FOXO) transcription factor family. FOXOs have been implicated in many cellular responses, including drug-induced resistance in cancer cells. However, FOXO-dependent acute phase resistance mediated by pictilisib, a potent small molecule PI3K inhibitor (PI3Ki), has not been studied. Here, we report that pictilisib-induced adaptive resistance is regulated by the FOXO-dependent rebound activity of receptor tyrosine kinases (RTKs) in mucinous colorectal adenocarcinoma (MCA) cells. The resistance mediated by PI3K inhibition involves the nuclear localization of FOXO and the altered expression of RTKs, including ErbB2, ErbB3, EphA7, EphA10, IR, and IGF-R1 in MCA cells. Further, in the presence of FOXO siRNA, the pictilisib-induced feedback activation of RTK regulators (pERK and pAKT) was altered in MCA cells. Interestingly, the combinational treatment of pictilisib (Pi3Ki) and FOXO1i (AS1842856) synergistically reduced MCA cell viability and increased apoptosis. These results demonstrate that pictilisib used as a single agent induces acute resistance, partly through FOXO1 inhibition. Therefore, overcoming PI3Ki single-agent adaptive resistance by rational design of FOXO1 and PI3K inhibitor combinations could significantly enhance the therapeutic efficacy of PI3K-targeting drugs in MCA cells.
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Xenou, Lydia, and Evangelia A. Papakonstanti. "p110δ PI3K as a therapeutic target of solid tumours." Clinical Science 134, no. 12 (June 2020): 1377–97. http://dx.doi.org/10.1042/cs20190772.
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Abstract From the time of first characterization of PI3K as a heterodimer made up of a p110 catalytic subunit and a regulatory subunit, a wealth of evidence have placed the class IA PI3Ks at the forefront of drug development for the treatment of various diseases including cancer. The p110α isoform was quickly brought at the centre of attention in the field of cancer research by the discovery of cancer-specific gain-of-function mutations in PIK3CA gene in a range of human solid tumours. In contrast, p110δ PI3K was placed into the spotlight of immunity, inflammation and haematologic malignancies because of the preferential expression of this isoform in leucocytes and the rare mutations in PIK3CD gene. The last decade, however, several studies have provided evidence showing that the correlation between the PIK3CA mutations and the response to PI3K inhibition is less clear than originally considered, whereas concurrently an unexpected role of p110δ PI3K in solid tumours has being emerging. While PIK3CD is mostly non-mutated in cancer, the expression levels of p110δ protein seem to act as an intrinsic cancer-causing driver in various solid tumours including breast, prostate, colorectal and liver cancer, Merkel-Cell carcinoma, glioblastoma and neurobalstoma. Furthermore, p110δ selective inhibitors are being studied as potential single agent treatments or as combination partners in attempt to improve cancer immunotherapy, with both strategies to shown great promise for the treatment of several solid tumours. In this review, we discuss the evidence implicating the p110δ PI3K in human solid tumours, their impact on the current state of the field and the potential of using p110δ-selective inhibitors as monotherapy or combined therapy in different cancer contexts.
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Maffei, Angelo, Giuseppe Lembo, and Daniela Carnevale. "PI3Kinases in Diabetes Mellitus and Its Related Complications." International Journal of Molecular Sciences 19, no. 12 (December 18, 2018): 4098. http://dx.doi.org/10.3390/ijms19124098.
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Recent studies have shown that phosphoinositide 3-kinases (PI3Ks) have become the target of many pharmacological treatments, both in clinical trials and in clinical practice. PI3Ks play an important role in glucose regulation, and this suggests their possible involvement in the onset of diabetes mellitus. In this review, we gather our knowledge regarding the effects of PI3K isoforms on glucose regulation in several organs and on the most clinically-relevant complications of diabetes mellitus, such as cardiomyopathy, vasculopathy, nephropathy, and neurological disease. For instance, PI3K α has been proven to be protective against diabetes-induced heart failure, while PI3K γ inhibition is protective against the disease onset. In vessels, PI3K γ can generate oxidative stress, while PI3K β inhibition is anti-thrombotic. Finally, we describe the role of PI3Ks in Alzheimer’s disease and ADHD, discussing the relevance for diabetic patients. Given the high prevalence of diabetes mellitus, the multiple effects here described should be taken into account for the development and validation of drugs acting on PI3Ks.
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Chen, Shiyi, Wenkang Huang, Xiaoyu Li, Lijuan Gao, and Yiping Ye. "Identifying Active Compounds and Mechanisms of Citrus changshan-Huyou Y. B. Chang against URTIs-Associated Inflammation by Network Pharmacology in Combination with Molecular Docking." Evidence-Based Complementary and Alternative Medicine 2022 (July 13, 2022): 1–10. http://dx.doi.org/10.1155/2022/2156157.
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Purpose. The ripe fruits of Citrus changshan-huyou, known as Quzhou Fructus Aurantii (QFA), have been commonly used for respiratory diseases. The purpose of this study was to investigate their active compounds and demonstrate their mechanism in the treatment of upper respiratory tract infections (URTIs) through network pharmacology and molecular docking. Methods. The prominent compounds of QFA were acquired from TCMSP database. Their targets were retrieved from SwissTargetPrediction database, and target genes associated with URTIs were collected from DisGeNET and GeneCards databases. The target protein-protein interaction (PPI) network was constructed by using STRING database and Cytoscape. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were enriched. Visual compound-target-pathway network was established with Cytoscape. The effects of compounds were verified on the inhibitory activities against phosphoinositide 3-kinases (PI3Ks). Finally, the molecular docking was carried out to confirm the binding affinity of the bioactive compounds and target proteins. Results. Five important active compounds, naringenin (NAR), tangeretin (TAN), luteolin (LUT), hesperetin (HES), and auraptene (AUR), were obtained. The enrichment analysis demonstrated that the pathways associated with inflammation mainly contained PI3K/Akt signalling pathway, TNF signalling pathway, and so on. The most important targets covering inflammation-related proteins might be PI3Ks. In vitro assays and molecular docking exhibited that TAN, LUT, and AUR acted as PI3Kγ inhibitors. Conclusion. The results revealed that QFA could treat URTIs through a multi-compound, multi-target, multi-pathway network, in which TAN, LUT, and AUR acted as PI3Kγ inhibitors, probably contributing to a crucial role in treatment of URTIs.
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Hutter, Grit, Yvonne Zimmermann, Anna-Katharina Zoellner, Philip Irrgang, Oliver Weigert, Wolfgang Hiddemann, and Martin Dreyling. "Combination of PI3K and PDPK1 Inhibitors Is Highly Effective in Mantle Cell Lymphoma." Blood 124, no. 21 (December 6, 2014): 3123. http://dx.doi.org/10.1182/blood.v124.21.3123.3123.
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Abstract Introduction: Mantle cell lymphoma (MCL), is a distinct lymphoma subtype with an aggressive clinical course and a median survival of 3-5 years. New emerging strategies include especially inhibitors of the PI3K/Akt/mTOR pathway which is constitutively activated in MCL and plays a critical role in tumor growth and survival. In the present study we analysed four different PI3K-Inhibitors (IPI-145, CAL101, A66 and TGX221) targeting different isoforms (PI3Kδ/γ, PI3Kδ, PI3Kα and PI3Kβ) for their effectiveness in MCL. Methods: MCL cell lines (Z-138, Mino-1, Granta-519, Jeko-1, Rec-1, Maver-1) were exposed to different PI3K-Inhibitors (IPI-145, CAL101, A66 and TGX221) with or without murine feeder layer (M210B4). The effect of drugs was evaluated by cell count (trypan-blue staining), cell metabolism (WST-assay or ONE-GloTMLuciferase assay for luciferized MCL cell lines), cell cycle (FACS) and apoptosis (Annexin V PE/7-AAD staining). Subsequently, combinations of PI3K-inhibitors and other target molecules (PDPK1: BX912, OSU03012, GSK2334470) were analysed. Western blot and mRNA analyses were performed after exposure to various inhibitors of the PI3K/Akt/mTOR pathway and correlated to sensitivity of cell lines. Finally, efficiency of drug combinations were confirmed in primary patient samples. Results: The PI3K inhibitor IPI145 (8,2%-62,4%) was most effective in MCL cell lines followed by A66 (0%-41,7%), TGX221 (0%-33,8%) and CAL101 (0%-28,2%) suggesting a higher efficiency by inhibiting multiple isoforms of PI3K. In patient samples IPI145 revealed also the highest cytotoxicity followed by CAL101, TGX221 and A66 (72,4%; 67,9%; 67,1% and 43,7%, respectively). Comparing various combinations of PI3K-inhibitors in MCL cell lines the simultaneous inhibition of α (A66) and δ (CAL101) isoforms achieved the highest reduction of cell count (65,2%). However, combined inhibition of both of PI3K δ and PDPK1 (BX912), led to a more efficient G2 arrest and higher rate of apoptosis due to the simultaneous dephosphorylation of members of the mTOR- and MAPK-pathways. Accordingly, the observed cytotoxicity was even higher (59%-87%) than for dual inhibition of PI3K (23%-60%). Currently, Western blot analyses are being expanded to further identify the differential mechanisms of PI3K inhibitor combinations. In addition, the presence of a murine feeder layer enhanced the effect of PI3K inhibitors in MCL cells nidated into the feederlayer because of higher levels of Akt phosphorylation possibly due to interaction with the microenvironment. Accordingly, this effect was not detectable in the supernatant cells. Conclusion: Based on our comparative analysis of PI3K inhibitors targeting of a and d isoforms appears to be the most efficient mechanism in MCL. However, this impact could be further increased by simultaneous inhibition of PDPK1. Western blot results suggest that these results are due to the inhibition of complementary pathways. Interestingly, the murine feeder layer enhanced the effect of PI3K inhibitors emphasizing the role of the microenvironment in the molecular mechanisms of targeted strategies. Disclosures Dreyling: Gilead: Gilead: speaker's honoraria Other.
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Courtney, Kevin D., Ryan B. Corcoran, and Jeffrey A. Engelman. "The PI3K Pathway As Drug Target in Human Cancer." Journal of Clinical Oncology 28, no. 6 (February 20, 2010): 1075–83. http://dx.doi.org/10.1200/jco.2009.25.3641.
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The phosphatidylinositol 3-kinase (PI3K) signaling axis impacts on cancer cell growth, survival, motility, and metabolism. This pathway is activated by several different mechanisms in cancers, including somatic mutation and amplification of genes encoding key components. In addition, PI3K signaling may serve integral functions for noncancerous cells in the tumor microenvironment. Consequently, therapeutics targeting the PI3K pathway are being developed at a rapid pace, and preclinical and early clinical studies are beginning to suggest specific strategies to effectively use them. However, the central role of PI3K signaling in a large array of diverse biologic processes raises concerns about its use in therapeutics and increases the need to develop sophisticated strategies for its use. In this review, we will discuss how PI3K signaling affects the growth and survival of tumor cells. From this vantage, we will consider how inhibitors of the PI3K signaling cascade, either alone or in combination with other therapeutics, can most effectively be used for the treatment of cancer.
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Brosinsky, Paulin, Julia Bornbaum, Björn Warga, Lisa Schulz, Klaus-Dieter Schlüter, Alessandra Ghigo, Emilio Hirsch, Rainer Schulz, Gerhild Euler, and Jacqueline Heger. "PI3K as Mediator of Apoptosis and Contractile Dysfunction in TGFβ1-Stimulated Cardiomyocytes." Biology 10, no. 7 (July 16, 2021): 670. http://dx.doi.org/10.3390/biology10070670.
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Background: TGFβ1 is a growth factor that plays a major role in the remodeling process of the heart by inducing cardiomyocyte dysfunction and apoptosis, as well as fibrosis thereby restricting heart function. TGFβ1 mediates its effect via the TGFβ receptor I (ALK5) and the activation of SMAD transcription factors, but TGFβ1 is also known as activator of phosphoinositide-3-kinase (PI3K) via the non-SMAD signaling pathway. The aim of this study was to investigate whether PI3K is also involved in TGFβ1–induced cardiomyocytes apoptosis and contractile dysfunction. Methods and Results: Incubation of isolated ventricular cardiomyocytes with TGFβ1 resulted in impaired contractile function. Pre-incubation of cells with the PI3K inhibitor Ly294002 or the ALK5 inhibitor SB431542 attenuated the decreased cell shortening in TGFβ1–stimulated cells. Additionally, TGFβ-induced apoptosis was significantly reduced by the PI3K inhibitor Ly294002. Administration of a PI3Kγ-specific inhibitor AS605240 abolished the TGFβ effect on apoptosis and cell shortening. This was also confirmed in cardiomyocytes from PI3Kγ KO mice. Induction of SMAD binding activity and the TGFβ target gene collagen 1 could be blocked by the PI3K inhibitor Ly294002, but not by the specific PI3Kγ inhibitor AS605240. Conclusions: TGFβ1-induced SMAD activation, cardiomyocyte apoptosis, and impaired cell shortening are mediated via both, the ALK5 receptor and PI3K, in adult cardiomyocytes. PI3Kγ specifically contributes to apoptosis induction and impairment of contractile function independent of SMAD signaling.
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Meadows, Sarah, Sorensen Rick, Yahiaoui Anella, Jia Liu, Li Li, Peng Yue, Christophe Queva, and Stacey Tannheimer. "Up-Regulation of the PI3K Signaling Pathway Mediates Resistance to Idelalisib." Blood 126, no. 23 (December 3, 2015): 3707. http://dx.doi.org/10.1182/blood.v126.23.3707.3707.
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Abstract Background: Idelalisib (Zydelig®), a potent and selective PI3Kδ inhibitor, was recently approved for the treatment of relapsed CLL, SLL and FL. PI3Kδ is critical for malignant B-cell proliferation, survival and homing, and inhibition results in a rapid decrease in lymphadenopathy and clinical response (Yang et al., Clin Can Res 2015). Although idelalisib is very potent in mitigating disease, most patients experience incomplete response and ultimately progress. To understand the mechanism of resistance, we screened ABC-DLBCL cell lines for sensitivity to idelalisib and selected TMD8, an ABC-DLBCL cell line, for the generation of idelalisib resistant cells. We report on the mechanisms of resistance and on downstream biomarkers associated with sensitivity to idelalisib in lymphoma cell lines. Methods: Growth inhibition to idelalisib or other inhibitors was assessed using CellTiterGlo viability assay (Promega) at 96 h. Idelalisib resistant line (TMD8R) was generated by continuous exposure to1μM idelalisib (~2x Cmax corrected for protein binding). A DMSO passage matched line was generated as control (TMD8S). Clonal isolates from pools were generated through 2 rounds of limiting dilution. Cell lines were analyzed by whole exome sequencing (WES, GeneWiz), RNASeq (Expression Analysis) and phosphoproteomics (MultiPathway PTMScan Direct, Cell Signaling Technologies). Protein expression was measured using Simple Western (Protein Simple) and SDS/PAGE Western blot. Results: TMD8 were sensitive to idelalisib and the pan PI3K inhibitor (GDC-0941) with an EC50 of 42 and 27nM, respectively, but not to PI3Kα (BYL-719) or PI3Kβ (AZD-6482) inhibitors, indicating that cell viability is mostly driven by PI3Kδ. TMD8 cells with acquired resistance to idelalisib (TMD8R) showed a loss of sensitivity to idelalisib, with a growth inhibition of 19% vs. 92% at 1μM as compared to TMD8S. No mutation in PIK3CD or other PI3K pathway members, including PTEN, was found in TMD8R clones by WES. In 8/8 TMD8R clones a dramatic reduction of PTEN protein expression was observed (9-fold) despite normal expression of PTEN mRNA by RNAseq (Figure 1A). Additionally 8/8 TMD8R clones showed a modest up-regulation of PIK3CG mRNA (2-fold) and protein (3-5 fold, Figure 1B). PIK3CD remained the most prevalent PI3K isoform expressed in all TMD8R clones (Figure 1C). TMD8R were cross-resistant to the dual PI3Kδ/γ inhibitor duvelisib (EC50 > 4 uM for TMD8R vs. EC50 = 58 nM for TMD8S). RNAseq analysis of idelalisib sensitive and resistant ABC-DLBCL cell lines showed that idelalisib treatment led to c-Myc mRNA down regulation in sensitive cell lines (TMD8 and Ri-1) but not in the resistant cell lines (U2932 and SU-DHL-8). In addition, expression of c-Myc target genes was unchanged in the TMDR. Analysis of phosphoproteins showed PI3K and MAPK pathway up-regulation in TMDR, compared to TMD8S, with increased expression of p-Akt T308, p-Akt S473, p-PDK1 S241, p-GSK3β S9 and p-ERK T202/Y204 (11-, 6-, 2-, 1- and 8-fold, respectively), providing a potential mechanism for the loss of c-Myc down regulation in resistant cells (Wen-Bin Tsai et al., Cancer Res, 2012). Other B-cell receptor signaling proteins (p-BTK Y223, p-SYK Y525/526, and p-STAT-5 Y694) were not detected or unchanged. TMD8R cells were cross resistant to the BTK inhibitors ibrutinib and ONO/GS-4059. Akt (MK-2206) or PDK1 (GSK233440) inhibitors were less potent in TMD8R vs. TMD8S cells, yet in combination with idelalisib at 1μM, their potency was restored to the level observed in TMD8S, indicating that resistant cells retain some dependency on the PI3Kδ. Conclusions: Resistance to idelalisib in the ABC-DLBCL cell line TMD8 was not acquired through de novo mutations. Rather loss of PTEN protein expression, modest up regulation of PI3Kγ, activation of the PI3K and MAPK pathway and loss of c-Myc down regulation by idelalisib were identified as potential mechanism of resistance. Treatment with agents targeting the PI3K pathway in combination with idelalisib may overcome resistance. Figure 1. Profiling of TMD8R Cells Reveal Increased PI3Kγ and PTEN loss. (A) Decreased expression of PTEN (9 fold) in TMD8R clones as compared to TMD8S (B) Overexpression of PI3Kγ (3-5 fold) in TMD8R clones as compared to TMD8S (C) PI3Kδ isoform is the highest expressed isoform in both TMD8S and TMD8R clones. Figure 1. Profiling of TMD8R Cells Reveal Increased PI3Kγ and PTEN loss. (A) Decreased expression of PTEN (9 fold) in TMD8R clones as compared to TMD8S (B) Overexpression of PI3Kγ (3-5 fold) in TMD8R clones as compared to TMD8S (C) PI3Kδ isoform is the highest expressed isoform in both TMD8S and TMD8R clones. Disclosures Meadows: Gilead Sciences: Employment, Other: Share holder. Rick:Gilead Sciences: Employment, Other: stock holder. Anella:Gilead Sciences: Employment, Other: Stock holder. Liu:Gilead Sciences: Employment, Other: stock holder. Li:Gilead Sciences: Employment, Other: Share holder. Yue:Gilead Sciences: Employment, Other: Share holder. Queva:Gilead Sciences: Other: Stock holder. Tannheimer:Gilead Sciences: Employment, Other: Share holder.
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Beck, Patrick, Kasen Reed Hutchings, Eileen Xu, Erin McDaid, Vincent Bui, Chinkal Patel, Jaime Solis, et al. "PIK3CB as a potential target to regulate chemosensitivity in glioblastoma." Journal of Clinical Oncology 41, no. 16_suppl (June 1, 2023): e14051-e14051. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.e14051.
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e14051 Background: Glioblastoma (GBM) is the most common primary central nervous system malignancy but exhibits universally poor outcomes in part due to chemoresistance. Temozolomide (TMZ) can significantly improve overall survival, but resistance mechanisms limit its consistent efficacy. The phosphoinositide 3 kinase (PI3K) pathway is involved in multiple TMZ resistance mechanisms and is highly druggable; however, pan-inhibition of its four grossly homologous but functionally distinct catalytic subunits (PIK3CA/B/D/G encode p110α/β/δ/γ, respectively) was unsuccessful clinically. Therefore, by understanding how the individual PI3K subunits regulate TMZ sensitivity, a more selective treatment strategy can be developed to combat chemoresistance. Methods: Differential expression of PI3K subunit genes was assessed using RNA sequencing (RNAseq) results obtained from public databases (e.g., DepMap, The Cancer Tissue Genome Atlas) for GBM cell lines and patient tumors expressing high or low O6-methylguanine-DNA-methyltransferase (MGMT), a DNA repair enzyme highly implicated in TMZ resistance. PI3K protein levels were assessed using immunohistochemistry of gliomas available at The Human Protein Atlas (THPA). PI3K gene expression was correlated with PI3K pathway activation, quantified as protein kinase B phosphorylation (pAKT). PI3K mRNAs and pAKT were then correlated with the half maximal inhibitory concentrations (IC50s) of TMZ in GBM cell lines to evaluate for a relationship between PI3K gene expression, PI3K pathway activity, and TMZ sensitivity. Finally, hazard ratios were used to compare PI3K gene expression in patient tumors with survival and response to chemotherapy to determine if expression was predictive of prognosis and/or chemosensitivity. Results: PIK3CB was the only PI3K gene enriched in both GBM cell lines and tumors, demonstrating significantly higher expression than all other PI3K genes in GBM (P < 0.0001), independent of MGMT levels. PIK3CB expression remained the highest even after controlling for GBM risk factors such as tumor recurrence, isocitrate dehydrogenase (IDH) mutations, molecular subtypes, or patient gender/age differences. Levels of the p110β protein were also significantly higher than those of other PI3K catalytic subunits (P < 0.001). PIK3CB expression was positively correlated with pAKT levels (P < 0.05), but only in cell lines and tumors with low MGMT activity. Both PIK3CB expression and pAKT levels correlated positively with TMZ IC50s (P < 0.05) in MGMT-deficient GBMs, suggesting an inverse relationship between PIK3CB and TMZ sensitivity. Finally, better prognosis and significant survival benefit with chemotherapy were both associated with lower levels of PIK3CB in MGMT-deficient patients. Conclusions: PIK3CB may selectively regulate chemoresistance in GBM, suggesting a role for p110β selective inhibition to improve chemosensitivity.
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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, no. 15_suppl (May 20, 2012): 4582. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.4582.
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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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Cao, Biyin, Jingyu Zhu, Man Wang, Yang Yu, Huixin Qi, Kunkun Han, Zubin Zhang, et al. "A Novel PI3K Inhibitor Identified By a High Throughput Virtual Screen Displays Potent Activity Against Multiple Myeloma." Blood 124, no. 21 (December 6, 2014): 4722. http://dx.doi.org/10.1182/blood.v124.21.4722.4722.
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Abstract The phosphatidylinositol-3-kinase (PI3K) has been developed as a promising target for the treatment of many cancers, including hematological malignancies, such as lymphoma, leukemia, and multiple myeloma (MM). Recent clinical trials have demonstrated Idelalisib, a specific PI3Kdelta inhibitor, reached a total 57% of response rate in relapsed indolent lymphoma and 72% of overall complete rate in relapsed chronic lymphocytic leukemia. MM remains fatal as a cancer of plasma cells because of lack of efficient drugs. Therefore, we tried to find novel PI3K inhibitors for MM therapy. To this end, we performed a high throughput virtual screen against 800,000 small molecule compounds using PI3Kγ as the analytic model and identified C98, a function unknown compound, as a potent inhibitor of PI3Ks. The cell-free enzymatic studies showed that C98 inhibited all class I PI3Ks at nano- or low micromolar concentrations but had no effects on AKT or mTOR activity. Molecular docking analysis revealed that C98 interfered with the ATP-binding pockets of PI3Ks by forming H-bonds and arene-H interactions with specific amino residues through which C98 specifically inhibited PI3K/AKT/mTOR signaling pathway, but had no effects on other kinases and proteins including IGF-1R, ERK, p38, c-Src, and STAT3. PTEN is a key negative modulator of the PI3K signaling pathway, but KIF did not show any induction of PTEN, thus further demonstrating that KIF is a selective PI3K inhibitor. Inhibition of PI3K by C98 led to myeloma cell apoptosis as shown activated caspase cascade signaling. Furthermore, oral administration of C98 delayed tumor growth in two independent human myeloma xenograft models in nude mice but did not show overt toxicity. Pharmacokinetic analysis revealed that C98 can be found in MM tissues at an average concentration up to 622.6 ng/g, suggesting that C98 can penetrate into the tumor tissues where it exerts its anti-myeloma activity. It also suggests C98 has a reliable oral activity. Therefore, through a high throughput virtual screen we identified a novel PI3K inhibitor that is orally active against multiple myeloma with great potential for further development. Disclosures No relevant conflicts of interest to declare.
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Lobo, Vítor, Ashly Rocha, Tarsila G. Castro, and Maria Alice Carvalho. "Synthesis of Novel 2,9-Disubstituted-6-morpholino Purine Derivatives Assisted by Virtual Screening and Modelling of Class I PI3K Isoforms." Polymers 15, no. 7 (March 29, 2023): 1703. http://dx.doi.org/10.3390/polym15071703.
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The phosphatidylinositol-3 kinase (PI3K) pathway is one of the most frequently activated pathogenic signalling cascades in a wide variety of cancers. In the last 15 years, there has been an increase in the search for selective inhibitors of the four class I isoforms of PI3K, as they demonstrate better specificity and reduced toxicity in comparison to existing inhibitors. A ligand-based and target-based rational drug design strategy was employed to build a virtual library of 105 new compounds. Through this strategy, the four isoforms were compared regarding their activity pocket availability, amino acid sequences, and prone interactions. Additionally, a known active scaffold was used as a molecular base to design new derivatives. The virtual screening of the resultant library toward the four isoforms points to the obtention of 19 selective inhibitors for the PI3Kα and PI3Kγ targets. Three selective ligands, one for α-isoform and two for γ-isoform, present a ∆ (∆Gbinding) equal or greater than 1.5 Kcal/mol and were identified as the most promising candidates. A principal component analysis was used to establish correlations between the affinity data and some of the physicochemical and structural properties of the ligands. The binding modes and interactions established by the selective ligands in the active centre of the α and γ isoforms of PI3K were also investigated. After modelling studies, a synthetic approach to generate selective ligands was developed and applied in synthesising a set of derivatives that were obtained in good to excellent yield.
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Guenther, Andreas, Renate Burger, Wolfram Klapper, Matthias Staudinger, and Martin Gramatzki. "Selective Inhibition Of The PI3K-Alpha Isoform Blocks Myeloma Cell Growth and Survival." Blood 122, no. 21 (November 15, 2013): 5364. http://dx.doi.org/10.1182/blood.v122.21.5364.5364.
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Abstract Introduction Both, the phosphoinositide-3kinase (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 exists in four isotypes (α - δ), the role of each of these isotypes in multiple myeloma (MM), however, is not defined. Therefore, we evaluated systematically the in vitroanti-myeloma activity of NVP-BYL719 (Novartis), a newly developed inhibitor highly selective for the PI3K α isoform, and compared it with the activity of other inhibitors targeting the PI3K/AKT/mToR signaling network at different sites. Since inhibition of mToRC1 may lead to PI3K activation by a feedback loop, we looked also at combinations of NVP-BYL719 and rapalogs. Materials and Methods An MTS based growth assay was used to measure growth inhibition of NVP-BYL719 in comparison to different inhibitors (the pan-PI3K inhibitors Ly294002 and NVP-BKM120, the dual PI3K/mToR inhibitor NVP-BEZ235, and the allosteric mToR inhibitors rapamycin and everolimus) on six human malignant plasma cell lines and two non-myeloma cell lines, K562 and Raji. Western blot analysis was used to confirm inhibitor activity and specificity. In addition, combinations of PI3K and mToR inhibitors were tested and antagonistic/synergistic activity was calculated with the CalcuSynTM (Biosoft) software. Results The selective PI3K alpha inhibitor NVP-BYL719 inhibited myeloma cell growth at a dose level (IC50 < 10 µM in 5/6 cell lines), where non-MM cell lines were not affected. Only cell line U266 was showed moderate sensitivity. The levels of the PI3K isoforms αwere comparable in all tested MM cell , as shown by Western blot. NVP-BYL719 blocked phosphorylation of AKT and of protein S6, an mToR downstream target. Of note, whenever rapamycin was combined with a PI3K inhibitor including NVP-BYL719, synergistic growth inhibition was seen, even in combination with the dual PI3K/mToR inhibitor NVP-BEZ235. Conclusions Here, the PI3Kα isoform is reported as being essential for the growth of myeloma cells. This provides the rationale for the therapeutic exploration of such isoform specific PI3K inhibitors in MM allowing dose intensification with less toxicity. Allosteric mToR inhibitors, already active in early clinical trials in MM patients may provide interesting combination partners for these PI3K-inhibitors. Disclosures: Guenther: Novartis: Consultancy. Gramatzki:Novartis: Consultancy.
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Jeong, Jae Seok, Jong Seung Kim, So Ri Kim, and Yong Chul Lee. "Defining Bronchial Asthma with Phosphoinositide 3-Kinase Delta Activation: Towards Endotype-Driven Management." International Journal of Molecular Sciences 20, no. 14 (July 18, 2019): 3525. http://dx.doi.org/10.3390/ijms20143525.
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Phosphoinositide 3-kinase (PI3K) pathways play a critical role in orchestrating the chronic inflammation and the structural changes of the airways in patients with asthma. Recently, a great deal of progress has been made in developing selective and effective PI3K-targeted therapies on the basis of a vast amount of studies on the roles of specific PI3K isoforms and fine-tuned modulators of PI3Ks in a particular disease context. In particular, the pivotal roles of delta isoform of class I PI3Ks (PI3K-δ) in CD4-positive type 2 helper T cells-dominant disorders such as asthma have been consistently reported since the early investigations. Furthermore, there has been great advancement in our knowledge of the implications of PI3K-δ in various facets of allergic inflammation. This has involved the airway epithelial interface, adaptive T and B cells, potent effector cells (eosinophils and neutrophils), and, more recently, subcellular organelles (endoplasmic reticulum and mitochondria) and cytoplasmic innate immune receptors such as NLRP3 inflammasome, all of which make this PI3K isoform an important druggable target for treating asthma. Defining subpopulations of asthma patients with PI3K-δ activation, namely PI3K-δ-driven asthma endotype, may therefore provide us with a novel framework for the treatment of the disease, particularly for corticosteroid-resistant severe form, an important unresolved aspect of the current asthma management. In this review, we specifically summarize the recent advancement of our knowledge on the critical roles of PI3K-δ in the pathogenesis of bronchial asthma.
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Chen, Yingwei, Bao-Can Wang, and Yongtao Xiao. "PI3K: A potential therapeutic target for cancer." Journal of Cellular Physiology 227, no. 7 (March 20, 2012): 2818–21. http://dx.doi.org/10.1002/jcp.23038.
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Rathinaswamy, Manoj K., Udit Dalwadi, Kaelin D. Fleming, Carson Adams, Jordan T. B. Stariha, Els Pardon, Minkyung Baek, et al. "Structure of the phosphoinositide 3-kinase (PI3K) p110γ-p101 complex reveals molecular mechanism of GPCR activation." Science Advances 7, no. 35 (August 2021): eabj4282. http://dx.doi.org/10.1126/sciadv.abj4282.
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The class IB phosphoinositide 3-kinase (PI3K), PI3Kγ, is a master regulator of immune cell function and a promising drug target for both cancer and inflammatory diseases. Critical to PI3Kγ function is the association of the p110γ catalytic subunit to either a p101 or p84 regulatory subunit, which mediates activation by G protein–coupled receptors. Here, we report the cryo–electron microscopy structure of a heterodimeric PI3Kγ complex, p110γ-p101. This structure reveals a unique assembly of catalytic and regulatory subunits that is distinct from other class I PI3K complexes. p101 mediates activation through its Gβγ-binding domain, recruiting the heterodimer to the membrane and allowing for engagement of a secondary Gβγ-binding site in p110γ. Mutations at the p110γ-p101 and p110γ–adaptor binding domain interfaces enhanced Gβγ activation. A nanobody that specifically binds to the p101-Gβγ interface blocks activation, providing a novel tool to study and target p110γ-p101–specific signaling events in vivo.
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Smith, Stephen F., Shannon E. Collins, and Pascale G. Charest. "Ras, PI3K and mTORC2 – three's a crowd?" Journal of Cell Science 133, no. 19 (October 1, 2020): jcs234930. http://dx.doi.org/10.1242/jcs.234930.
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ABSTRACTThe Ras oncogene is notoriously difficult to target with specific therapeutics. Consequently, there is interest to better understand the Ras signaling pathways to identify potential targetable effectors. Recently, the mechanistic target of rapamycin complex 2 (mTORC2) was identified as an evolutionarily conserved Ras effector. mTORC2 regulates essential cellular processes, including metabolism, survival, growth, proliferation and migration. Moreover, increasing evidence implicate mTORC2 in oncogenesis. Little is known about the regulation of mTORC2 activity, but proposed mechanisms include a role for phosphatidylinositol (3,4,5)-trisphosphate – which is produced by class I phosphatidylinositol 3-kinases (PI3Ks), well-characterized Ras effectors. Therefore, the relationship between Ras, PI3K and mTORC2, in both normal physiology and cancer is unclear; moreover, seemingly conflicting observations have been reported. Here, we review the evidence on potential links between Ras, PI3K and mTORC2. Interestingly, data suggest that Ras and PI3K are both direct regulators of mTORC2 but that they act on distinct pools of mTORC2: Ras activates mTORC2 at the plasma membrane, whereas PI3K activates mTORC2 at intracellular compartments. Consequently, we propose a model to explain how Ras and PI3K can differentially regulate mTORC2, and highlight the diversity in the mechanisms of mTORC2 regulation, which appear to be determined by the stimulus, cell type, and the molecularly and spatially distinct mTORC2 pools.
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Gong, Grace Q., Jackie D. Kendall, James M. J. Dickson, Gordon W. Rewcastle, Christina M. Buchanan, William A. Denny, Peter R. Shepherd, and Jack U. Flanagan. "Combining properties of different classes of PI3Kα inhibitors to understand the molecular features that confer selectivity." Biochemical Journal 474, no. 13 (June 26, 2017): 2261–76. http://dx.doi.org/10.1042/bcj20161098.
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Phosphoinositide 3-kinases (PI3Ks) are major regulators of many cellular functions, and hyperactivation of PI3K cell signalling pathways is a major target for anticancer drug discovery. PI3Kα is the isoform most implicated in cancer, and our aim is to selectively inhibit this isoform, which may be more beneficial than concurrent inhibition of all Class I PI3Ks. We have used structure-guided design to merge high-selectivity and high-affinity characteristics found in existing compounds. Molecular docking, including the prediction of water-mediated interactions, was used to model interactions between the ligands and the PI3Kα affinity pocket. Inhibition was tested using lipid kinase assays, and active compounds were tested for effects on PI3K cell signalling. The first-generation compounds synthesized had IC50 (half maximal inhibitory concentration) values >4 μM for PI3Kα yet were selective for PI3Kα over the other Class I isoforms (β, δ and γ). The second-generation compounds explored were predicted to better engage the affinity pocket through direct and water-mediated interactions with the enzyme, and the IC50 values decreased by ∼30-fold. Cell signalling analysis showed that some of the new PI3Kα inhibitors were more active in the H1047R mutant bearing cell lines SK-OV-3 and T47D, compared with the E545K mutant harbouring MCF-7 cell line. In conclusion, we have used a structure-based design approach to combine features from two different compound classes to create new PI3Kα-selective inhibitors. This provides new insights into the contribution of different chemical units and interactions with different parts of the active site to the selectivity and potency of PI3Kα inhibitors.
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Narayanankutty, Arunaksharan. "PI3K/ Akt/ mTOR Pathway as a Therapeutic Target for Colorectal Cancer: A Review of Preclinical and Clinical Evidence." Current Drug Targets 20, no. 12 (August 22, 2019): 1217–26. http://dx.doi.org/10.2174/1389450120666190618123846.
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Background: Phosphoinositide 3-kinase (PI3Ks) is a member of intracellular lipid kinases and involved in the regulation of cellular proliferation, differentiation and survival. Overexpression of the PI3K/Akt/mTOR signalling has been reported in various forms of cancers, especially in colorectal cancers (CRC). Due to their significant roles in the initiation and progression events of colorectal cancer, they are recognized as a striking therapeutic target. Objective: The present review is aimed to provide a detailed outline on the role of PI3K/Akt/mTOR pathway in the initiation and progression events of colorectal cancers as well as its function in drug resistance. Further, the role of PI3K/Akt/mTOR inhibitors alone and in combination with other chemotherapeutic drugs, in alleviating colorectal cancer is also discussed. The review contains preclinical and clinical evidence as well as patent literature of the pathway inhibitors which are natural and synthetic in origin. Methods: The data were obtained from PubMed/Medline databases, Scopus and Google patent literature. Results: PI3K/Akt/mTOR signalling is an important event in colorectal carcinogenesis. In addition, it plays significant roles in acquiring drug resistance as well as metastatic initiation events of CRCs. Several small molecules of natural and synthetic origin have been found to be potent inhibitors of CRCs by effectively downregulating the pathway. Data from various clinical studies also support these pathway inhibitors and several among them are patented. Conclusion: Inhibitors of the PI3K/mTOR pathway have been successful for the treatment of primary and metastatic colorectal cancers, rendering the pathway as a promising clinical cancer therapeutic target.
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Kang, Byung Woog, and Ian Chau. "Molecular target: pan-AKT in gastric cancer." ESMO Open 5, no. 5 (September 2020): e000728. http://dx.doi.org/10.1136/esmoopen-2020-000728.
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The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signalling pathway is involved in multiple cellular processes, including cell survival, proliferation, differentiation, metabolism and cytoskeletal reorganisation. The downstream effectors of this PI3K pathway are also essential for maintaining physiologic homeostasis, commonly dysregulated in most solid tumours. AKT is the key regulator in PI3K/AKT/mTOR signalling, interacting with multiple intracellular molecules. AKT activation subsequently leads to a number of potential downstream effects, and its aberrant activation results in the pathogenesis of cancer. Accordingly, as an attractive therapeutic target for cancer treatment, several AKT inhibitors are currently under development and in multiple stages of clinical trials for various types of malignancy, including gastric cancer (GC). Therefore, the authors review the significance of AKT and recent studies on AKT inhibitors in GC, focusing on the scientific background with the potential to improve treatment outcomes.
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Bheemanaboina, Rammohan R. Y. "Isoform-Selective PI3K Inhibitors for Various Diseases." Current Topics in Medicinal Chemistry 20, no. 12 (June 1, 2020): 1074–92. http://dx.doi.org/10.2174/1568026620666200106141717.
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Phosphoinositide 3-kinases (PI3Ks) are a family of ubiquitously distributed lipid kinases that control a wide variety of intracellular signaling pathways. Over the years, PI3K has emerged as an attractive target for the development of novel pharmaceuticals to treat cancer and various other diseases. In the last five years, four of the PI3K inhibitors viz. Idelalisib, Copanlisib, Duvelisib, and Alpelisib were approved by the FDA for the treatment of different types of cancer and several other PI3K inhibitors are currently under active clinical development. So far clinical candidates are non-selective kinase inhibitors with various off-target liabilities due to cross-reactivities. Hence, there is a need for the discovery of isoform-selective inhibitors with improved efficacy and fewer side-effects. The development of isoform-selective inhibitors is essential to reveal the unique functions of each isoform and its corresponding therapeutic potential. Although the clinical effect and relative benefit of pan and isoformselective inhibition will ultimately be determined, with the development of drug resistance and the demand for next-generation inhibitors, it will continue to be of great significance to understand the potential mechanism of isoform-selectivity. Because of the important role of type I PI3K family members in various pathophysiological processes, isoform-selective PI3K inhibitors may ultimately have considerable efficacy in a wide range of human diseases. This review summarizes the progress of isoformselective PI3K inhibitors in preclinical and early clinical studies for anticancer and other various diseases.
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Uche, Uzodinma U., Ann R. Piccirillo, Shunsuke Kataoka, Stephanie J. Grebinoski, Louise M. D’Cruz, and Lawrence P. Kane. "PIK3IP1/TrIP restricts activation of T cells through inhibition of PI3K/Akt." Journal of Experimental Medicine 215, no. 12 (November 14, 2018): 3165–79. http://dx.doi.org/10.1084/jem.20172018.
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Phosphatidylinositol-3 kinases (PI3Ks) modulate cellular growth, proliferation, and survival; dysregulation of the PI3K pathway can lead to autoimmune disease and cancer. PIK3IP1 (or transmembrane inhibitor of PI3K [TrIP]) is a putative transmembrane regulator of PI3K. TrIP contains an extracellular kringle domain and an intracellular domain with homology to the inter-SH2 domain of the PI3K regulatory subunit p85, but the mechanism of TrIP function is poorly understood. We show that both the kringle and p85-like domains are necessary for TrIP inhibition of PI3K and that TrIP is down-modulated from the surface of T cells during T cell activation. In addition, we present evidence that the kringle domain may modulate TrIP function by mediating oligomerization. Using an inducible knockout mouse model, we show that TrIP-deficient T cells exhibit more robust activation and can mediate clearance of Listeria monocytogenes infection faster than WT mice. Thus, TrIP is a negative regulator of T cell activation and may represent a novel target for immune modulation.
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Goncalves, Marcus D., and Azeez Farooki. "Management of Phosphatidylinositol-3-Kinase Inhibitor-Associated Hyperglycemia." Integrative Cancer Therapies 21 (January 2022): 153473542110731. http://dx.doi.org/10.1177/15347354211073163.
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Phosphatidylinositol-3-kinase (PI3K) pathway hyperactivation has been associated with the development of cancer and treatment resistance. PI3K inhibitors are now used to treat hormone receptor-positive (HR+), human epidermal growth factor receptor-2–negative (HER2−), PIK3CA-mutated advanced breast cancer. Hyperglycemia, a frequently observed adverse event with PI3K inhibitors (PI3Ki), is regarded as an on-target effect because inhibition of the PI3K pathway has been shown to decrease glucose transport and increase glycogenolysis and gluconeogenesis. PI3Ki-induced hyperglycemia results in a compensatory increase in insulin release, which has been shown to reduce the efficacy of treatment by reactivating the PI3K pathway in preclinical models. Patients with an absolute or relative deficiency in insulin, and those with insulin resistance or pancreatic dysfunction, may experience exacerbated or prolonged hyperglycemia. Therefore, the effective management of PI3Ki-associated hyperglycemia depends on early identification of patients at risk, frequent monitoring to allow prompt recognition of hyperglycemia and its sequelae, and initiating appropriate management strategies. Risk factors for the development of hyperglycemia include older age (≥75 years), overweight/obese at baseline, and family history of diabetes. Consultation with an endocrinologist is recommended for patients considered high risk. The management of PI3Ki-induced hyperglycemia requires an integrative approach that combines diets low in carbohydrates and glucose-lowering medications. Medications that do not affect the PI3K pathway are preferred as the primary and secondary agents for the management of hyperglycemia. These include metformin, sodium-glucose co-transporter 2 inhibitors, thiazolidinediones, and α-glucosidase inhibitors. Insulin should only be considered as a last-line agent for PI3Ki-associated hyperglycemia due to its stimulatory effect of PI3K signaling. Clinical studies show that alpelisib-associated hyperglycemia is reversible and manageable, rarely leading to treatment discontinuation. Management of PI3Ki-associated hyperglycemia in patients with breast cancer should focus on the prevention of acute and subacute complications of hyperglycemia, allowing patients to remain on anticancer treatment longer.
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Thillai, Kiruthikah, Debashis Sarker, and Claire Wells. "PAK4 as a potential therapeutic target in pancreatic ductal adenocarcinoma (PDAC)." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e23139-e23139. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e23139.
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e23139 Background: PDAC is an aggressive cancer and metastatic spread requires reorganization of the actin cytoskeleton, a process dependent on Rho family GTPases and their interaction with downstream effectors. p21 activated kinases (PAK1-6) are effectors of Rho GTPases Cdc42 and Rac, and play a key role in cell migration and survival. PAK4 can be amplified in PDAC and can reciprocally activate the PI3K pathway. Hepatocyte growth factor (HGF), via c-Met, is an established activator of PAK4 and the PI3K pathway and may promote PDAC invasion. We hypothesized that there is a link between PAK4 and PI3K downstream of HGF and thus PAK4 is a potential therapeutic target in PDAC. Methods: Several invasive PDAC cell lines were used including PaTu 8988T, PaTu 8988S, Capan 1, Panc 1 and PaTu 8902. SiRNA transfection allowed transient loss of PAK4 and cell migration was measured using 2D time lapse microscopy. An organotypic model consisting of PDAC and stromal cells within an extracellular gel of collagen was developed to assess 3D invasion. Immunofluorescence staining of cytokeratin and smooth muscle actin allowed analysis of depth of invasion. Protein expression was measured using western blotting and protein interaction by pulldown assays. Results: Treatment with the c-Met ligand HGF increased migration speed, persistence of direction and importantly PDAC invasion. HGF also stimulated the phosphorylation of several proteins within the PI3K pathway including AKT and PRAS40. Loss of PAK4 expression resulted in a concomitant loss in PI3K signalling. Moreover, PAK4 directly binds to the p85α subunit of PI3K in PDAC cells. Reduced PAK4 expression in PDAC cells suppressed HGF-induced migration, and PAK4 depletion significantly inhibited the invasion response to HGF. Conclusions: We demonstrate a novel link between PAK4, PI3K and AKT, and show the significant effects of PAK4 on PDAC cell polarity, migration and invasion. Our results strongly support further investigation of PAK4 as a therapeutic target in PDAC, particularly given the minimal impact of PI3K-AKT pathway inhibitors in PDAC to date.
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Smith, Greg C., Wee Kiat Ong, Gordon W. Rewcastle, Jackie D. Kendall, Weiping Han, and Peter R. Shepherd. "Effects of acutely inhibiting PI3K isoforms and mTOR on regulation of glucose metabolism in vivo." Biochemical Journal 442, no. 1 (January 27, 2012): 161–69. http://dx.doi.org/10.1042/bj20111913.
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In in vitro studies class-I PI3Ks (phosphoinositide 3-kinases), class-II PI3Ks and mTOR (mammalian target of rapamycin) have all been described as having roles in the regulation of glucose metabolism. The relative role each plays in the normal signalling processes regulating glucose metabolism in vivo is less clear. Knockout and knockin mouse models have provided some evidence that the class-I PI3K isoforms p110α, p110β, and to a lesser extent p110γ, are necessary for processes regulating glucose metabolism and appetite. However, in these models the PI3K activity is chronically reduced. Therefore we analysed the effects of acutely inhibiting PI3K isoforms alone, or PI3K and mTOR, on glucose metabolism and food intake. In the present study impairments in glucose tolerance, insulin tolerance and increased hepatic glucose output were observed in mice treated with the pan-PI3K/mTOR inhibitors PI-103 and NVP-BEZ235. The finding that ZSTK474 has similar effects indicates that these effects are due to inhibition of PI3K rather than mTOR. The p110α-selective inhibitors PIK75 and A66 also induced these phenotypes, but inhibitors of p110β, p110δ or p110γ induced only minor effects. These drugs caused no significant effects on BMR (basal metabolic rate), O2 consumption or water intake, but BEZ235, PI-103 and PIK75 did cause a small reduction in food consumption. Surprisingly, pan-PI3K inhibitors or p110α inhibitors caused reductions in animal movement, although the cause of this is not clear. Taken together these studies provide pharmacological evidence to support a pre-eminent role for the p110α isoform of PI3K in pathways acutely regulating glucose metabolism.
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Jia, Wen-Qing, Xiao-Yan Feng, Ya-Ya Liu, Zhen-Zhen Han, Zhi Jing, Wei-Ren Xu, and Xian-Chao Cheng. "Identification of Phosphoinositide-3 Kinases Delta and Gamma Dual Inhibitors Based on the p110δ/γ Crystal Structure." Letters in Drug Design & Discovery 17, no. 6 (June 29, 2020): 772–86. http://dx.doi.org/10.2174/1570180816666190730163431.
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Background: Phosphoinositide-3 kinases (PI3Ks) are key signaling molecules that affect a diverse array of biological processes in cells, including proliferation, differentiation, survival, and metabolism. The abnormal activity of PI3K signals is closely related to the occurrence of many diseases, which has become a very promising drug target, especially for the treatment of cancer. PI3Kδ/γ inhibitors can reduce toxicity concerns for chronic indications such as asthma and rheumatoid arthritis compared with pan PI3Ks inhibitors. Methods: With the aim of finding more effective PI3Kδ/γ dual inhibitors, virtual screening, ADMET prediction Molecular Dynamics (MD) simulations and MM-GBSA were executed based on the known p110δ/γ crystal structure. Compound ZINC28564067 with high docking score and low toxicity was obtained. Results: By MD simulations and MM-GBSA, we could observe that ZINC28564067 had more favorable conformation binding to the PI3Kδ/γ than the original ligands. Conclusion: The results provided a rapid approach for the discovery of novel PI3Kδ/γ dual inhibitors which might be a potential anti-tumor lead compound.
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Zhang, Xuewei, Masumi Ishibashi, Kazuyuki Kitatani, Shogo Shigeta, Hideki Tokunaga, Masafumi Toyoshima, Muneaki Shimada, and Nobuo Yaegashi. "Potential of Tyrosine Kinase Receptor TIE-1 as Novel Therapeutic Target in High-PI3K-Expressing Ovarian Cancer." Cancers 12, no. 6 (June 26, 2020): 1705. http://dx.doi.org/10.3390/cancers12061705.
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Tyrosine kinase receptor TIE-1 plays a critical role in angiogenesis and blood-vessel stability. In recent years, increased TIE-1 expression has been observed in many types of cancers; however, the biological significance and underlying mechanisms remain unknown. Thus, in the present study, we investigated the tumor biological functions of TIE-1 in ovarian cancer. The treatment of SKOV3 ovarian-cancer cells with siRNA against TIE-1 decreased the expression of key molecules in the PI3K/Akt signaling pathway, such as p110α and phospho-Akt, suggesting that TIE-1 is related to the PI3K/Akt pathway. Furthermore, the knockdown of TIE-1 significantly decreased cell proliferation in high-PI3K-expressing cell lines (SKOV3, CAOV3) but not low-PI3K-expressing cell lines (TOV112D, A2780). These results suggested that inhibition of TIE-1 decreases cell growth in high-PI3K-expressing cells. Moreover, in low-PI3K-expressing TOV112D ovarian-cancer cells, TIE-1 overexpression induced PI3K upregulation and promoted a PI3K-mediated cell proliferative phenotype. Mechanistically, TIE-1 participates in cell growth and proliferation by regulating the PI3K/Akt signaling pathway. Taken together, our findings strongly implicate TIE-1 as a novel therapeutic target in high-PI3K-expressing ovarian-cancer cells.
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Rezende, Denise C., Lorena Zaida Pacheco, Luis Arthur F. Pelloso, Maria L. Chauffaille, Marçal C. A. Silva, Elisa Kimura, Rafael L. Casaes-Rodrigues, Helena Segreto, Mihoko Yamamoto, and Daniella Marcia Maranhao Bahia Kerbauy. "PI3K/AKT Pathway as a Potential Therapeutic Target In Myelodysplastic Syndrome." Blood 116, no. 21 (November 19, 2010): 1871. http://dx.doi.org/10.1182/blood.v116.21.1871.1871.
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Abstract Abstract 1871 Introduction: PI3K/AKT pathway is involved in cell growth, proliferation and apoptosis. A key downstream effector is the phosphorylated serine-threonine Akt (p-AKT). Constitutive activation of PI3K/AKT has been observed in solid tumours and leukemic cells. Inhibition of PI3K/AKT activity, results in apoptosis in cell lines (CL) after treatment with different compounds, e.g. deguelin, a natural product from the leguminous Mundulea sericea, with antitumour effects. Aims: To evaluate PI3K/AKT activation in MDS patients and its therapeutic potential in MDS. Methods: PI3K/AKT activation was evaluated by flow cytometry (FC) using an alexa-fluor 488-antibody Ser 473 p-AKT (Cell Signalling Technology). A triple immunostaining procedure using CD45-PerCP and CD34-PE was used for p-AKT expression in CD34+ primary samples. The p-AKT activity was determined using Kolmogorov-Smirnov test (D). CD34+ cells from healthy donors and Jurkat cells were used as negative and positive controls respectively. Apoptosis (determined by Annexin V and PI/7AAD) and cell cycle arrest (using RNAse and PI) were determined following treatments with LY294002 (50uM), and deguelin (100-500nM) in P-39 myeloid leukemia cell line, with constitutive PI3K/AKT activation. Apoptosis was determined in bone marrow mononuclear cells and CD34+ cells from MDS patients with the same treatments. To evaluate in vivo activity of deguelin, we used a xenotransplant model. Briefly, NODSCID mice were injected intrafemurally with P-39 CL and 12 days post transplant a three week-course of treatment, every other day, was started (deguelin 4mg/Kg, n=3 vs vehicle, n=3). Results: P-39 CL showed constitutive PI3K/AKT activation with levels significantly higher than in CD34+cells from controls (median±SD= 0.73. Disclosures: No relevant conflicts of interest to declare.
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Blunt, Matthew D., Matthew J. Carter, Marta Larrayoz, Maria Montserrat Aguilar, Sarah Murphy, Mark Reynolds, Thomas Tipton, et al. "The Dual PI3K/mTOR Inhibitor PF-04691502 Induces Substantial Apoptosis in Chronic Lymphocytic Leukemia Cells in Vitro and Prolongs Survival in the Eµ-TCL1 Mouse Model." Blood 124, no. 21 (December 6, 2014): 832. http://dx.doi.org/10.1182/blood.v124.21.832.832.
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Abstract Pharmacological inhibition of specific B cell receptor signalling pathways within chronic lymphocytic leukemia (CLL) cells offers the potential for improved therapeutic options with reduced off target toxicity. Idelalisib, the PI3Kδ selective inhibitor, has been approved for CLL and significantly improved overall survival among patients with relapsed CLL in combination with rituximab compared to rituximab alone. In addition to PI3Kδ however, there are three other Class I PI3K isoforms, PI3Kα, PI3Kβ and PI3Kγ, with PI3Kα known to have a role in CLL survival and chemotaxis. In neutrophils, functional redundancy between PI3K isoforms is evident, with inhibition of at least three PI3K isoforms required for maximal apoptosis. Inhibition of mTOR is known to induce cell cycle arrest and apoptosis in CLL cells, however prolonged inhibition of mTOR results in activation of a positive feedback loop resulting in PI3K\Akt reactivation. To overcome these caveats, pan PI3K inhibition alongside mTOR inhibition may achieve superior cytotoxicity against CLL cells compared to PI3Kδ or mTOR inhibition alone. We therefore sought to investigate the effect of a dual pan PI3K and mTOR inhibitor, PF-04691502, on primary CLL cells and in the Eµ-TCL1 mouse model of CLL. Twenty five primary CLL samples were treated with PF-04691502 and downstream signalling and subsequent apoptosis assessed by immunoblotting and Annexin V/PI staining respectively. In primary CLL cells, PF-04691502 induced 80% apoptosis after 24 hours at 10µM concentration. PF-04691502 had an IC50 value of 1µM as assessed by Annexin V/PI staining, with minimal toxicity to normal human B or T cells and a trend towards more specific killing in unmutated CLL (p=0.09) compared to mutated CLL. PF-04691502 inhibited both soluble and immobilised anti-IgM induced signalling and overcame anti-IgM induced survival signals. PF-04691502 abrogated CXCL12 induced signalling and impaired subsequent CLL migration towards the chemokine in a transwell chemotaxis assay. Finally, PF-04691502 was able to overcome protection from co-culture with stroma inducing significant apoptosis of CLL cells when added continuously and in wash out experiments. To assess the effect of PF-04691502 in vivo, twenty Eµ-TCL1 mice were inoculated with tumour cells and after day 21 dosed once daily with vehicle, 5mg/kg or 10mg/kg PF-04691502 for a further 14 days. Mice were assessed for leukemic cell counts, spleen size and white blood cell count throughout the duration of the experiment. The effect of PF-04691502 on B cell receptor and chemokine receptor induced signalling in ex vivo Eµ-TCL1 cells was assessed by immunoblotting. Near identical results to the CLL data above were observed. Using Eµ-TCL1 cells isolated from the spleen, PF-04691502 was shown to profoundly inhibit anti-IgM and CXCL12 induced signalling and chemotaxis as well as induce substantial apoptosis as measured by Annexin V/PI staining. Therefore, we subsequently assessed the effect of PF-04691502 in vivo using this model. Mice treated with PF-04691502 displayed a transient increase in leukemic cell numbers in the blood persisting for 1-4 days, followed by a reduction to levels significantly below that of the vehicle control. The whole white blood cell count remained stable in the PF-04691502 treated mice during the course of treatment, whilst the vehicle treated mice showed significant increases in tumour load up to 40×106 cells/ml 33 days post inoculation. Spleen sizes increased steadily over time in the control mice, whilst PF-04691502 treatment prevented this. After 33 days, PF-04691502 treated mice had spleen sizes comparable to non tumor-recipient control animals. In addition, CD5+ B220+ Eµ-TCL1 cells were significantly reduced in the bone marrow, spleen and lymph nodes following PF-04691502 treatment compared to control mice (p=0.0198; p< 0.0001; p=0.0151 respectively). These results demonstrate that PF-04691502 induces substantial apoptosis of primary CLL cells in vitro and significantly prolongs survival in an in vivo murine model of CLL. Such data indicate that dual pan PI3K/mTOR inhibitors may prove efficacious in the treatment of CLL patients. Disclosures No relevant conflicts of interest to declare.
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Chen, Yu-Chen Enya, Melinda Lea Burgess, Antje Blumenthal, Sally Mapp, Peter Mollee, Devinder Gill, and Nicholas Andrew Saunders. "Activation of Fc Gamma Receptor-Dependent Responses to Therapeutic Antibodies By Nurse like Cells Requires PI3Kdelta." Blood 132, Supplement 1 (November 29, 2018): 3128. http://dx.doi.org/10.1182/blood-2018-99-109719.
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Abstract There is a continued reliance on antibody therapies for treating chronic lymphocytic leukaemia (CLL). Whilst the inclusion of antibody therapies in many standard treatment regimes results in good outcomes, acquired resistance remains a significant clinical challenge for many CLL patients resulting in insensitivity to the antibody treatment. Thus, understanding the mechanisms driving treatment resistance is likely to lead to therapies to reverse resistance and improve patient outcomes. Earlier studies from our laboratory have shown that resistance to therapeutic antibodies, in CLL, is due to a reduced ability of monocyte derived macrophages (MDMs) to participate in FcγR-dependent antitumour responses (e.g. ADCC and antibody-dependent phagocytosis (ADP). In this regard, we recently showed that SYK and BTK activation are downstream of the FcγRs (Oncogene, 36(17):2366-2376, 2017). Moreover, we showed that signalling through the FcγR pathway was reduced in antibody-resistant MDMs and could be reversed using inhibitors of SHIP1. These studies indicated that knowledge of FcγR signalling could exploited to reverse resistance. Unfortunately, knowledge of the exact signalling events controlling FcγR activity in MDMs from CLL patients is unclear. In this study we investigated the involvement of PI3K isoforms in FcγR-dependent ADCC and ADP in MDMs from CLL patients. PI3K isoforms have been shown to be important pathway regulators for immune-receptor function in various immune cells such as T cells, B cells and NK cells as well as in cancerous cells. In the first instance, I examined the expression of PI3K isoforms in MDMs from CLL patients. This showed that PI3Kα, β, and δ are expressed in MDMs whereas PI3Kγ is below the limit of detection. Next, I examined the involvement of the different PI3K isoforms to contribute to FcγR-dependent ADCC by MDMs. For this we used a suite of isoform-selective inhibitors to target each PI3K isoform and examined their effect on ADCC responses by MDMs. The PI3Kδ-selective inhibitor, idelalisib and the pan PI3K inhibitor BKM120 (Buparlisib) were able to inhibit ADCC responses to the CD20-targeting therapeutic antibody, obinutuzumab. Similarly, both buparlisib and idelalisib were able to inhibit AKT phosphorylation at concentrations that also inhibited ADCC. In contrast. None of the other isoform-selective inhibitors were able to suppress ADCC responses to obinutuzumab. These studies have been repeated using isoform-specific siRNAs. This is the first report to show that PI3Kδ is involved in FcγR signalling in MDMs from CLL patients or in MDMs from any tumour type. Based on these findings we conclude that PI3Kδ is a critical effector molecule for antitumour responses to therapeutic antibodies in CLL. Disclosures Mollee: Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Gill:Pharma: Membership on an entity's Board of Directors or advisory committees.
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Bosch, Ana, Zhiqiang Li, Anna Bergamaschi, Haley Ellis, Eneda Toska, Aleix Prat, Jessica J. Tao, et al. "PI3K inhibition results in enhanced estrogen receptor function and dependence in hormone receptor–positive breast cancer." Science Translational Medicine 7, no. 283 (April 15, 2015): 283ra51. http://dx.doi.org/10.1126/scitranslmed.aaa4442.
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Activating mutations ofPIK3CAare the most frequent genomic alterations in estrogen receptor (ER)–positive breast tumors, and selective phosphatidylinositol 3-kinase α (PI3Kα) inhibitors are in clinical development. The activity of these agents, however, is not homogeneous, and only a fraction of patients bearingPIK3CA-mutant ER-positive tumors benefit from single-agent administration. Searching for mechanisms of resistance, we observed that suppression of PI3K signaling results in induction of ER-dependent transcriptional activity, as demonstrated by changes in expression of genes containing ER-binding sites and increased occupancy by the ER of promoter regions of up-regulated genes. Furthermore, expression ofESR1mRNA and ER protein were also increased upon PI3K inhibition. These changes in gene expression were confirmed in vivo in xenografts and patient-derived models and in tumors from patients undergoing treatment with the PI3Kα inhibitor BYL719. The observed effects on transcription were enhanced by the addition of estradiol and suppressed by the anti-ER therapies fulvestrant and tamoxifen. Fulvestrant markedly sensitized ER-positive tumors to PI3Kα inhibition, resulting in major tumor regressions in vivo. We propose that increased ER transcriptional activity may be a reactive mechanism that limits the activity of PI3K inhibitors and that combined PI3K and ER inhibition is a rational approach to target these tumors.
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Giulino Roth, Lisa, Herman van Besien, Anna Rodina, Tony Taldone, Hediye Erdjument-Bromage, Matthew J. Barth, Gabriela Chiosis, and Ethel Cesarman. "Targeting the Hsp90 Oncoproteome in Burkitt Lymphoma." Blood 126, no. 23 (December 3, 2015): 592. http://dx.doi.org/10.1182/blood.v126.23.592.592.
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Abstract Introduction: Novel therapies are urgently needed in pediatric Burkitt lymphoma (pBL) where the survival for relapsed disease is less than 20%. Heat shock protein 90 (Hsp90) is molecular chaperone that protects proteins from proteolytic degradation including oncogenic signaling complexes. The clinical development of broad-spectrum Hsp90 inhibitors has previously been limited by suboptimal target inhibition and off-target toxicities. PU-H71 is a next-generation Hsp90 inhibitor that preferentially targets tumor enriched (te-Hsp90), the functionally distinct pool of Hsp90 present in tumor cells. PU-H71 is not toxic to normal B-cells and has demonstrated pre-clinical efficacy in diffuse large B-cell lymphoma, but has not been studied in Burkitt lymphoma. In the current study, we evaluated te-Hsp90 as a potential therapeutic target in pediatric Burkitt lymphoma. Methods and Results: To evaluate overall Hsp90 protein expression in primary pBL tumors we performed immunohistochemistry on a tissue microarray. Fifty-three of 59 cases (90%) demonstrated high levels of Hsp90 expression defined as >90% tumor cell positivity (Fig. 1A). To evaluate the sensitivity of pBL to te-Hsp90 inhibition we performed in-vitro viability assays with the ATP-based CellTiter-Glo¨ in a panel of pBL cell lines (Ramos, DG-75, Raji, Namalwa, Daudi, Jiyoye, CA-46, Raji 2R, Raji 4RH) and in-vivo studies with a Ramos xenograft model of pBL. pBL cells were sensitive to inhibition by PU-H71 with IC50s in the low nanomolar range (151-337nM, Fig 1B). The Raji 2R and Raji 4RH pBL cell lines with acquired resistance to chemotherapy (Czuczman et al, Clin Cancer Res 2008) were also sensitive to PU-H71 (IC50 175-181nM). In contrast, normal peripheral blood lymphocytes were resistant (IC50 >37,000nM). In pBL xenograft studies, PU-H71 decreased tumor volume (p<0.01, Fig. 1C) and prolonged survival (p<0.01, Fig. 1D). To evaluate the targets of PU-H71 in pBL we performed high affinity capture followed by proteomic analysis using mass spectrometry. Cellular lysates from pBL cell lines were incubated with PU-H71 conjugated agarose beads and the cargo was subject to tandem mass spectrometry. Data was analyzed using Ingenuity Pathway Analysis¨. PI3K and mTOR signaling were among the top networks identified. Given the data supporting a crucial role for PI3K in BL (Sanders et al, Cancer Cell 2012), we further investigated protein targets in this pathway. We found a significant number of proteins in the mTOR (p<0.0001) and PI3K (p<0.0001) signaling pathways including ERK, mTOR, and multiple isoforms of PI3K (p110-β; p110-γ, p110-δ). PI3K targets were validated by pull-downs with PU-H71 conjugated beads (Fig 2A). To investigate the activity of PI3K inhibition in pBL we evaluated a panel of PI3K inhibitors in pBL. Agents with a narrow spectrum of PI3K isoform inhibition such as idelalisib (p110δ inhibition) and IPI-145 (p110 δ and γ inhibition) did not have activity in pBL. In contrast, agents that broadly target PI3K/mTOR such as BEZ235 (pan PI3K and mTOR inhibition) and BKM120 (pan PI3K inhibition) demonstrated activity (IC50 35nM-2602nM). Based on this we concluded that PI3K inhibition is effective in pBL only when multiple components of the pathway are targeted. We hypothesized that PU-H71 will therefore synergize with PI3K inhibitors through dual targeting of PI3K signaling. To test this we evaluated the combination of PU-H71 + BKM-120 and PU-H71 + BEZ235 in four pBL cell lines (Ramos, Namalwa, Daudi, DG-75). The combined response at 48-72 hours was evaluated using the Chou-Talalay method. Both combinations were synergistic in 3 of 4 cell lines with a combinatorial index at the IC50 of <1 (CI 0.44-0.79, Fig. 2B). Conclusion: Our work demonstrates that Hsp90 is over-expressed in primary pBL tumors and that te-Hsp90 inhibition with PU-H71 is toxic to pBL in-vitro and in-vivo. The oncoprotein targets of Hsp90 in pBL include multiple components of the PI3K/mTOR signaling pathway, highlighting the importance of this pathway in pBL. The anti-lymphoma activity of PU-H71 is synergistic with pan-PI3K inhibition as well as dual PI3K/mTOR inhibition. Overall this work provides support for te-Hsp90 as a therapeutic target in BL and suggests the potential for combination therapy with PU-H71 and inhibitors of PI3K/mTOR. Disclosures Cesarman: Weill Cornell Medical College: Patents & Royalties: applied for patent for 6-ETI.
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Popova, Nadezhda V., and Manfred Jücker. "The Role of mTOR Signaling as a Therapeutic Target in Cancer." International Journal of Molecular Sciences 22, no. 4 (February 9, 2021): 1743. http://dx.doi.org/10.3390/ijms22041743.
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The aim of this review was to summarize current available information about the role of phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling in cancer as a potential target for new therapy options. The mTOR and PI3K/AKT/mTORC1 (mTOR complex 1) signaling are critical for the regulation of many fundamental cell processes including protein synthesis, cell growth, metabolism, survival, catabolism, and autophagy, and deregulated mTOR signaling is implicated in cancer, metabolic dysregulation, and the aging process. In this review, we summarize the information about the structure and function of the mTOR pathway and discuss the mechanisms of its deregulation in human cancers including genetic alterations of PI3K/AKT/mTOR pathway components. We also present recent data regarding the PI3K/AKT/mTOR inhibitors in clinical studies and the treatment of cancer, as well the attendant problems of resistance and adverse effects.
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Dent, Paul, Steven Grant, Paul B. Fisher, and David T. Curiel. "PI3K: a rational target for ovarian cancer therapy?" Cancer Biology & Therapy 8, no. 1 (January 2009): 27–30. http://dx.doi.org/10.4161/cbt.8.1.7365.
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Malik, Nazma, Thomas Macartney, Annika Hornberger, Karen E. Anderson, Hannah Tovell, Alan R. Prescott, and Dario R. Alessi. "Mechanism of activation of SGK3 by growth factors via the Class 1 and Class 3 PI3Ks." Biochemical Journal 475, no. 1 (January 2, 2018): 117–35. http://dx.doi.org/10.1042/bcj20170650.
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Derailment of the PI3K-AGC protein kinase signalling network contributes to many human diseases including cancer. Recent work has revealed that the poorly studied AGC kinase family member, SGK3, promotes resistance to cancer therapies that target the Class 1 PI3K pathway, by substituting for loss of Akt kinase activity. SGK3 is recruited and activated at endosomes, by virtue of its phox homology domain binding to PtdIns(3)P. Here, we demonstrate that endogenous SGK3 is rapidly activated by growth factors such as IGF1, through pathways involving both Class 1 and Class 3 PI3Ks. We provide evidence that IGF1 enhances endosomal PtdIns(3)P levels via a pathway involving the UV-RAG complex of hVPS34 Class 3 PI3K. Our data point towards IGF1-induced activation of Class 1 PI3K stimulating SGK3 through enhanced production of PtdIns(3)P resulting from the dephosphorylation of PtdIns(3,4,5)P3. Our findings are also consistent with activation of Class 1 PI3K promoting mTORC2 phosphorylation of SGK3 and with oncogenic Ras-activating SGK3 solely through the Class 1 PI3K pathway. Our results highlight the versatility of upstream pathways that activate SGK3 and help explain how SGK3 substitutes for Akt following inhibition of Class 1 PI3K/Akt pathways. They also illustrate robustness of SGK3 activity that can remain active and counteract physiological conditions or stresses where either Class 1 or Class 3 PI3K pathways are inhibited.
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Mabrouk, Mohammed El, Quy N. Diep, Karim Benkirane, Rhian M. Touyz, and Ernesto L. Schiffrin. "SAM68: a downstream target of angiotensin II signaling in vascular smooth muscle cells in genetic hypertension." American Journal of Physiology-Heart and Circulatory Physiology 286, no. 5 (May 2004): H1954—H1962. http://dx.doi.org/10.1152/ajpheart.00134.2003.
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We investigated whether phosphatidylinositol 3-kinase (PI3K) and 68-kDa Src associated during mitosis (SAM68) are involved in angiotensin II (ANG II) growth signaling in vascular smooth muscle cells (VSMCs) from spontaneously hypertensive rats (SHR). PI3K activity was assessed by measuring the phosphorylation of the regulatory subunit p85α and kinase activity of the catalytic 110-kDa subunit of PI3K. The PI3K-SAM68 interaction was assessed by coimmunoprecipitation, and SAM68 activity was evaluated by poly(U) binding. SAM68 expression was manipulated by SAM68 antisense oligonucleotide transfection. VSMC growth was evaluated by measuring [3H]leucine and [3H]thymidine incorporation as indexes of protein and DNA synthesis, respectively. ANG II increased the phosphorylation of p85α and kinase activity of the 110-kDa PI3K subunit in VSMCs from SHR and transiently increased p85α-SAM68 association. In Wistar-Kyoto (WKY) rat cells, ANG II increased SAM68 phosphorylation without influencing poly(U) binding. In SHR, ANG II did not influence SAM68 phosphorylation but increased SAM68 binding to poly(U). ANG II stimulated phosphoinositol phosphate synthesis by PI3K in SAM68 immunoprecipitates in both groups, with significantly enhanced effects in SHR. Inhibition of PI3K, using the selective inhibitor LY-294002, and downregulation of SAM68, by antisense oligonucleotides, significantly decreased ANG II-stimulated incorporation of [3H]leucine and [3H]thymidine in VSMCs, showing the functional significance of PI3K and SAM68. Our data demonstrate that PI3K and SAM68 are involved in ANG II signaling and that SAM68 is differentially regulated in VSMCs from SHR. These processes may contribute to the enhanced ANG II signaling and altered VSMC growth in SHR.
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Yan, Zhao, Guangmei Liu, Yang Yang, Ling Chen, Ying Shang, and Qian Hong. "Identifying mechanisms of Epimedii Folium against Alzheimer’s disease via a network pharmacology approach Epimedii Folium treats Alzheimer’s disease via PI3K-AKT." European Journal of Inflammation 19 (January 2021): 205873922110414. http://dx.doi.org/10.1177/20587392211041435.
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To elucidate the mechanism of the multi-target action of Epimedii Folium on Alzheimer’s disease, this study focuses on the analysis of network pharmacology. Based on a bioinformatics approach, this study obtained the effective components of Epimedium through the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, predicted the compound targets through the Pharmapper and Swiss target prediction database and then through Gene Expression Omnibus Datasets and Therapeutic Target Database. We collected and analysed of heral and disease targets, constructed the network. Through the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, Gene Ontology enrichment, then the key targets and pathways of Epimedii Folium to cope with Alzheimer’s disease have been identified. Twenty-three bioactive components and 477 potential target genes of Epimedii Folium were identified. A total of 1612 target diseases were identified. Through network module analysis, 30 hub target genes were identified. Through enrichment analysis of the KEGG pathway, hub target genes were largely enriched in the PI3K-AKT signaling pathway. Through the analysis of network pharmacology, it was found that Epimedii Folium might play the role of multi-compound and multi-target therapy through the PI3K-AKT signaling pathway. These findings provide helpful directions for future clinical studies.
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Gao, Haotian, Zaolin Li, Kai Wang, Yuhan Zhang, Tong Wang, Fang Wang, and Youjun Xu. "Design, Synthesis, and Biological Evaluation of Sulfonamide Methoxypyridine Derivatives as Novel PI3K/mTOR Dual Inhibitors." Pharmaceuticals 16, no. 3 (March 20, 2023): 461. http://dx.doi.org/10.3390/ph16030461.
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Phosphatidylinositol 3-kinase (PI3K) plays an important role in cell proliferation, survival, migration, and metabolism, and has become an effective target for cancer treatment. Meanwhile, inhibiting both PI3K and mammalian rapamycin receptor (mTOR) can simultaneously improve the efficiency of anti-tumor therapy. Herein, a series of 36 sulfonamide methoxypyridine derivatives with three different aromatic skeletons were synthesized as novel potent PI3K/mTOR dual inhibitors based on a scaffold hopping strategy. Enzyme inhibition assay and cell anti-proliferation assay were employed to assess all derivatives. Then, the effects of the most potent inhibitor on cell cycle and apoptosis were performed. Furthermore, the phosphorylation level of AKT, an important downstream effector of PI3K, was evaluated by Western blot assay. Finally, molecular docking was used to confirm the binding mode with PI3Kα and mTOR. Among them, 22c with the quinoline core showed strong PI3Kα kinase inhibitory activity (IC50 = 0.22 nM) and mTOR kinase inhibitory activity (IC50 = 23 nM). 22c also showed a strong proliferation inhibitory activity, both in MCF-7 cells (IC50 = 130 nM) and HCT-116 cells (IC50 = 20 nM). 22c could effectively cause cell cycle arrest in G0/G1 phase and induce apoptosis of HCT-116 cells. Western blot assay showed that 22c could decrease the phosphorylation of AKT at a low concentration. The results of the modeling docking study also confirmed the binding mode of 22c with PI3Kα and mTOR. Hence, 22c is a promising PI3K/mTOR dual inhibitor, which is worthy of further research in the area.
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Zapevalova, Maria V., Ekaterina S. Shchegravina, Irina P. Fonareva, Diana I. Salnikova, Danila V. Sorokin, Alexander M. Scherbakov, Alexander A. Maleev, et al. "Synthesis, Molecular Docking, In Vitro and In Vivo Studies of Novel Dimorpholinoquinazoline-Based Potential Inhibitors of PI3K/Akt/mTOR Pathway." International Journal of Molecular Sciences 23, no. 18 (September 17, 2022): 10854. http://dx.doi.org/10.3390/ijms231810854.
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A (series) range of potential dimorpholinoquinazoline-based inhibitors of the PI3K/Akt/mTOR cascade was synthesized. Several compounds exhibited cytotoxicity towards a panel of cancer cell lines in the low and sub-micromolar range. Compound 7c with the highest activity and moderate selectivity towards MCF7 cells which express the mutant type of PI3K was also tested for the ability to inhibit PI3K-(signaling pathway) downstream effectors and associated proteins. Compound 7c inhibited the phosphorylation of Akt, mTOR, and S6K at 125–250 nM. It also triggered PARP1 cleavage, ROS production, and cell death via several mechanisms. Inhibition of PI3Kα was observed at a concentration of 7b 50 µM and of 7c 500 µM and higher, that can indicate minority PI3Kα as a target among other kinases in the titled cascade for 7c. In vivo studies demonstrated an inhibition of tumor growth in the colorectal tumor model. According to the docking studies, the replacement of the triazine core in gedatolisib (8) by a quinazoline fragment, and incorporation of a (hetero)aromatic unit connected with the carbamide group via a flexible spacer, can result in more selective inhibition of the PI3Kα isoform.
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Wang, Xiaohui, Lin Zhou, Tao Zhang, Hui Chen, Xinhao Song, and Feng Wang. "Effect and Mechanism of Schizandrin A in the Treatment of Liver Cancer Using Network Pharmacology, Molecular Docking, and Target Validation." Natural Product Communications 18, no. 5 (May 2023): 1934578X2311769. http://dx.doi.org/10.1177/1934578x231176916.
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Background Liver cancer is a common threat to human health. Schizandrin A (SA) has certain therapeutic effect on liver cancer, but its related mechanism of action is not clear. Elucidating this mechanism is of great significance for the development of drugs to target liver cancer. Objective The objective is to study the effect and mechanism of SA on liver cancer. Methods The potential targets of SA in the treatment of liver cancer were screened based on network pharmacology, and the core targets were further screened by protein network interaction. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis was performed based on the core targets to find the key pathways of action. The results obtained for key targets and pathways were verified in vitro by pharmacological experiments with HepG2 cells. Specifically, an Enzyme Linked Immunosorbent assay (ELISA) kit was used to detect the content of key indicators (interleukin-1 (IL-1), Tumor Necrosis Factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-10 (IL-10), superoxide dismutase [SOD], malondialdehyde [MDA], interferon (IFN), and Glutathione peroxidase (GSH-px)), Quantitative Real-time Polymerase Chain Reaction (qRT-PCR) was used to detect the key messenger Ribonucleic Acid (mRNA) (phosphatidylinositol 3 kinase (PI3K), protein kinase B (Akt), vascular endothelial growth factor A (VEGFA), and Transforming Growth Factor Beta-1 (TGF-β1)) after drug intervention, and Western blotting (WB) detected the expression of key target proteins (p-PI3K, PI3K, p-Akt, and Akt). Results The results showed that SA mainly acts on IL-1β, TNF-α, IL-6, IL-10, SOD, MDA, TGF-β1, IFN, and VEGFA, affecting the PI3K-Akt signaling pathway and playing an anti-inflammatory role in the treatment of liver cancer. The experimental results showed that SA significantly reduced the inflammation level of HepG2 cells; improved the oxidative stress state (decreasing SOD level and increasing MDA level of cells); downregulated TGF-β1, VEGFA, PI3K, and Akt mRNA levels; and inhibited the expression of the PI3K-Akt signaling pathway. Conclusions SA has a significant anti-HepG2 effect, which may be achieved by reducing inflammation levels, improving oxidative stress state, and inhibiting the PI3K-Akt pathway.
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Li, Jun-min, Zi-zhen Xu, Ai-hua Wang, and Jiong Hu. "Activation of PI3K/Akt/mTOR Pathway in Diffuse Large B-Cell Lymphomas: Clinical Significance and Inhibitory Effect by Rituximab." Blood 114, no. 22 (November 20, 2009): 1934. http://dx.doi.org/10.1182/blood.v114.22.1934.1934.
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Abstract Abstract 1934 Poster Board I-957 A better understanding of the biology of diffuse large B cell lymphoma(DLBCL) is needed in the developement of potential therapeutic agents that target specific intracellular pathway. In this study, expression of the important members of PI3K/Akt/mTOR signaling pathway and their clinical significance were investigated in 73 cases of DLBCL. Immunohistochemical analyses showed that activation of Akt and its downstream targets such as p-p70S6K, p-4E-BP1, YB-1 and Mcl-1 were present in DLBCL cases. Activation of PI3K/Akt/mTOR pathway was related to poor disease outcome in DLBCL patients treated by CHOP but not in those treated by R-CHOP. Rituximab combined with chemotherapy could down-regulate PI3K/Akt/mTOR activation and reverse its negative effect on chemotherapy-treated patients. The effect of Rituximab alone or combined with the mTOR inhibitor Rapamycin was further evaluated in DLBCL cell line SUDHL-4. Rituximab combined with Rapamycin possessed synergic effect in down-regulating PI3K/Akt/mTOR signaling pathway, inhibited proliferation and caused G1 arrest in DLBCL cell line. The results showed that PI3K/Akt/mTOR signaling pathway activation presented in DLBCL may be considered as a prognostic biomarker and a promising target for therapeutic intervention. Disclosures: No relevant conflicts of interest to declare.
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Caforio, Matteo, Emmanuel de Billy, Biagio De Angelis, Stefano Iacovelli, Concetta Quintarelli, Valeria Paganelli, and Valentina Folgiero. "PI3K/Akt Pathway: The Indestructible Role of a Vintage Target as a Support to the Most Recent Immunotherapeutic Approaches." Cancers 13, no. 16 (August 11, 2021): 4040. http://dx.doi.org/10.3390/cancers13164040.
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Pathologic activation of PI3Ks and the subsequent deregulation of its downstream signaling pathway is among the most frequent events associated with cellular transformation, cancer, and metastasis. PI3Ks are also emerging as critical factors in regulating anti-tumor immunity by either promoting an immunosuppressive tumor microenvironment or by controlling the activity and the tumor infiltration of cells involved in the immune response. For these reasons, significant pharmaceutical efforts are dedicated to inhibiting the PI3K pathway, with the main goal to target the tumor and, at the same time, to enhance the anti-tumor immunity. Recent immunotherapeutic approaches involving the use of adoptive cell transfer of autologous genetically modified T cells or immune check-point inhibitors showed high efficacy. However, mechanisms of resistance to these kinds of therapy are emerging, due in part to the inhibition of effector T cell functions exerted by the immunosuppressive tumor microenvironment. Here, we first describe how inhibition of PI3K/Akt pathway contribute to enhance anti-tumor immunity and further discuss how inhibitors of the pathway are used in combination with different immunomodulatory and immunotherapeutic agents to improve anti-tumor efficacy.
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Knight, Z. A., and K. M. Shokat. "Chemically targeting the PI3K family." Biochemical Society Transactions 35, no. 2 (March 20, 2007): 245–49. http://dx.doi.org/10.1042/bst0350245.
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PI3K (phosphoinositide 3-kinase) is a key regulator of cell growth, metabolism and survival. The frequent activation of the PI3K pathway in cancer has stimulated widespread interest in identifying potent and selective inhibitors of PI3K isoforms. The present paper highlights recent progress in identifying such molecules and the challenges that remain for efforts to pharmacologically target the PI3K family.
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Zuo, Ximeng, Xiaoguang Shi, Xuedan Zhang, Zhenzhou Chen, Zhenrui Yang, Xiaojuan Pan, Rui Lai, and Ze Zhao. "Postoperative Ileus with the Topical Application of Tongfu Decoction Based on Network Pharmacology and Experimental Validation." Evidence-Based Complementary and Alternative Medicine 2022 (March 28, 2022): 1–12. http://dx.doi.org/10.1155/2022/2347419.
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Objective. Postoperative gastrointestinal dysfunction is a common and important complication of surgery. This study aimed to explore the key pharmacological mechanisms of Tongfu decoction in treating postoperative ileus (POI). Methods. The active ingredients of Tongfu decoction and their targets were screened using the TCMSP database and STITCH and SwissTargetPrediction databases, respectively. The GeneCards and DisGeNET databases were used to obtain POI dysfunction-related therapeutic targets. After screening, a drug-active-ingredient-therapeutic target network was constructed and the key target functional enrichment analysis was carried out. The Sprague–Dawley rats with POI were used for in vivo experimental verification. The serum levels of IL-1β, IL-6, IL-10, IFN-γ, and MCP-1 were measured after surgery using enzyme-linked immunosorbent assay. The Western blot analysis was used to determine the expression of key proteins of the PI3K-Akt signaling pathway in colon tissues. Results. An interaction network was constructed containing 7 Chinese medicine components, 36 compounds, and 85 target proteins. The functional enrichment analysis showed that the target proteins mainly acted on the POI through the PI3K-Akt signaling pathway. In in vivo experiments, Tongfu decoction had a promoting effect on the serum level of IL-10, an inhibitory effect on the serum levels of IL-1β and CCL2, and an inhibitory effect on the local expression of PI3K, pAkt, and mTOR in colon tissue. In addition, the Tongfu decoction increased the intestinal ink advancing rate. Conclusion. Nonoral Tongfu decoction can also be used to treat POI; its mechanism is affected by IL-10 and IL-1β.The inhibition of the PI3K-Akt signaling pathway affected the treatment with Tongfu decoction by inducing an immune-inflammatory storm in POI.