Search results for: CAL-101 Mechanisms: PI3K-p110-delta-specific inhibitor
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Synergistic Effects of PI3K and c-Myc Co-targeting in Acute Leukemia: Shedding New Light on Resistance to Selective PI3K-δ Inhibitor CAL-101.Enthusiasms into the application of PI3K-δ inhibitor CAL-101 has been muted due to the over-activation of compensatory molecules. Our results delineated that c-Myc suppression using 10058-F4 enhanced CAL-101 cytotoxicity in less sensitive cells through different mechanisms based on p53 status; while CAL-101-plus-10058-F4 induced G1 arrest in wild-type p53-expressing leukemic cells, no conspicuous increase in G1 was noted in U937 cells harboring mutant p53. Conclusively, this study shed lights on the role of c-Myc oncoprotein in acute leukemia cells sensitivity to PI3K inhibitor and outlined that the combination of c-Myc inhibitor and CAL-101 may be a promising therapeutic approach in leukemia.
2303 related Products with: Synergistic Effects of PI3K and c-Myc Co-targeting in Acute Leukemia: Shedding New Light on Resistance to Selective PI3K-δ Inhibitor CAL-101.BGT-226 Mechanisms: PI3K BYL-719 Mechanisms: PI3K- XL-147 Mechanisms: PI3K i CAL-101 Mechanisms: PI3K- PX-866 Mechanisms: PI3K i GDC-0980 Mechanisms: PI3K GDC-0941 Mechanisms: PI3K IPI-145 (INK-1197) Mechan BEZ-235 Mechanisms: PI3K PKI-587 (PF-05212384) Mec BKM-120 Mechanisms: PI3K GSK-2636771 Mechanisms: P
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Theoretical studies on the selectivity mechanisms of PI3Kδ inhibition with marketed idelalisib and its derivatives by 3D-QSAR, molecular docking, and molecular dynamics simulation.Phosphoinositide 3-kinases (PI3Ks) are crucial for cell proliferation, metabolism, motility, and cancer progression. Since the selective PI3Kδ inhibitor, idelalisib, was firstly approved by the FDA in 2014, large numbers of selective PI3Kδ inhibitors have been reported, but the detailed mechanisms of selective inhibition to PI3Kδ for idelalisib or its derivatives have not been well addressed. In this study, 3D-QSAR with COMFA, molecular docking, and molecular dynamic (MD) simulations was used to explore the binding modes between PI3Kδ and idelalisib derivatives. Firstly, a reliable COMFA model (q = 0.59, ONC = 8, r = 0.966) was built and the contour maps showed that the electrostatic field had more significant contribution to the bioactivities of inhibitors. Secondly, two molecular docking methods including rigid receptor docking (RRD) and induced fit docking (IFD) were employed to predict the docking poses of all the studied inhibitors and revealed the selective binding mechanisms. And then, the results of the MD simulation and the binding free energy decomposition verified that the binding of PI3Kδ/inhibitors was mainly contributed from hydrogen bonding and hydrophobic interactions and some key residues for selective binding were highlighted. Finally, based on the models developed, 14 novel inhibitors were optimized and some showed satisfactory predicted bioactivity. Taken together, the results provided by this study may facilitate the rational design of novel and selective PI3Kδ inhibitors. Graphical abstract .
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IGF1R as druggable target mediating PI3K-δ inhibitor resistance in a murine model of chronic lymphocytic leukemia.Targeted therapy is revolutionizing the treatment of cancers, but resistance evolves against these therapies and derogates their success. The phosphatidylinositol 3-kinase delta (PI3K-δ) inhibitor idelalisib has been approved for treatment of chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma, but the mechanisms conferring resistance in a subset of patients are unknown. Here, we modeled resistance to PI3K-δ inhibitor in vivo using a serial tumor transfer and treatment scheme in mice. Whole-exome sequencing did not identify any recurrent mutation explaining resistance to PI3K-δ inhibitor. In the murine model, resistance to PI3K-δ inhibitor occurred as a result of a signaling switch mediated by consistent and functionally relevant activation of insulin-like growth factor 1 receptor (IGF1R), resulting in enhanced MAPK signaling in the resistant tumors. Overexpression of in vitro demonstrated its prominent role in PI3K-δ inhibitor resistance. IGF1R upregulation in PI3K-δ inhibitor-resistant tumors was mediated by functional activation and enhanced nuclear localization of forkhead box protein O1 transcription factors and glycogen synthase kinase 3β. In human CLL, high expression was associated with trisomy 12. CLL cells from an idelalisib-treated patient showed decreased sensitivity to idelalisib in vitro concomitant with enhanced MAPK signaling and strong upregulation of IGF1R upon idelalisib exposure. Thus, our results highlight that alternative signaling cascades play a predominant role in the resistance and survival of cancer cells under PI3K-δ inhibition. We also demonstrate that these pathway alterations can serve as therapeutic targets, because inhibition of IGF1R offered efficacious salvage treatment of PI3K-δ inhibitor-resistant tumors in vitro and in vivo.
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Pulmonary adverse events related to idelalisib therapy: A single centre experience.Idelalisib is a potent and selective inhibitor of the PI3Kδ approved since September 2014 for the treatment of several types of B cell malignancies. Pulmonary adverse events related to idelalisib are an emerging serious adverse event. We report here a single centre cohort of 16 patients who initiated idelalisib as routine treatment. Five of them experienced severe pulmonary adverse events related to idelalisib therapy. Comparison of the 5 patients with severe pulmonary events versus the 11 patients without identified no predisposing factors. Severe pulmonary adverse events were related to infectious pneumonia and/or to a drug-induced pneumonitis. The mechanisms of idelalisib-associated pneumonitis are unknown but consistent with the drug-induced pneumonitis described with mTOR inhibitors. Indeed, by inhibiting PI3Kδ, idelalisib also inhibits the mTOR pathway. Clinicians should be aware that any idelalisib-treated patient who presents with pulmonary symptoms should be evaluated for pneumonitis. Corticosteroids should be considered in addition to anti-infective therapy in case of severe pneumonitis or persistent pulmonary symptoms despite adequate antibiotic therapy.
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Idelalisib promotes Bim-dependent apoptosis through AKT/FoxO3a in hepatocellular carcinoma.Idelalisib, a selective PI3Kδ inhibitor, has been approved by the FDA for chronic lymphocytic leukemia/small lymphocytic lymphoma treatment and for follicular lymphoma treatment when combined with rituximab. However, the mechanisms of effective action of idelalisib in hepatocellular carcinoma (HCC) remain unclear. In the current study, we aimed to investigate how idelalisib inhibits the growth of HCC cells and enhances the effects of other chemotherapeutic drugs. Our results show that idelalisib treatment promotes Bim induction in HCC via the FoxO3a pathway following PI3K/AKT inactivation. Moreover, our results show that Bim is required for idelalisib-mediated apoptosis in HCC. Idelalisib also synergizes with sorafenib or doxorubicin to induce significant apoptosis in HCC, and Bim is also necessary for the induction of apoptosis by cotreatment. Furthermore, a xenograft experiment reveals that the Bim deficiency abolishes apoptosis and antitumor effects of idelalisib in vivo. In summary, our results indicate a key role of Bim in mediating the antitumor effects of idelalisib in HCC. Our results also support the clinical significance of the drug.
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Spotlight on copanlisib and its potential in the treatment of relapsed/refractory follicular lymphoma: evidence to date.The importance of the phosphatidylinositol-3-kinase (PI3K) pathway in cell survival and proliferation has made it an attractive target in cancer therapy. The development of small molecule inhibitors for the PI3K pathway continues to provide treatment alternatives across a range of malignancy types. Several agents, including idelalisib, copanlisib and duvelisib, not only inhibit the PI3K pathway, but also have effects on associated mechanisms including the ATK and mTOR pathways. The advent of PI3K-specific small molecular inhibitors has led to increased efficacy with avoidance of an excessive toxicity profile. Key enzymes of the PI3K pathway exhibit differing expression in tissue types and roles in tumor pathogenesis. Copanlisib (BAY 80-6946) is a pan-specific PI3K small molecule inhibitor for four key isoforms with increased activity against PI3Kα and PI3Kδ, both important in B-cell malignancies. Follicular lymphoma is one of the most common indolent B-cell non-Hodgkin lymphomas worldwide. Follicular lymphoma like other indolent B-cell non-Hodgkin lymphomas is beleaguered by high relapse rates and the need for subsequent therapy options. Based on efficacy and a limited toxicity profile, copanlisib received accelerated US Food and Drug Administration approval for the treatment of adult patients with relapsed follicular lymphoma following two lines of therapy. Here, we review the development of copanlisib and the role of this agent in the treatment of follicular lymphoma.
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Phosphoinositide 3-kinase δ inhibition promotes antitumor responses but antagonizes checkpoint inhibitors.Multiple modes of immunosuppression restrain immune function within tumors. We previously reported that phosphoinositide 3-kinase δ (PI3Kδ) inactivation in mice confers resistance to a range of tumor models by disrupting immunosuppression mediated by regulatory T cells (Tregs). The PI3Kδ inhibitor idelalisib has proven highly effective in the clinical treatment of chronic lymphocytic leukemia and the potential to extend the use of PI3Kδ inhibitors to nonhematological cancers is being evaluated. In this work, we demonstrate that the antitumor effect of PI3Kδ inactivation is primarily mediated through the disruption of Treg function, and correlates with tumor dependence on Treg immunosuppression. Compared with Treg-specific PI3Kδ deletion, systemic PI3Kδ inactivation is less effective at conferring resistance to tumors. We show that PI3Kδ deficiency impairs the maturation and reduces the capacity of CD8+ cytotoxic T lymphocytes (CTLs) to kill tumor cells in vitro, and to respond to tumor antigen-specific immunization in vivo. PI3Kδ inactivation antagonized the antitumor effects of tumor vaccines and checkpoint blockade therapies intended to boost the CD8+ T cell response. These findings provide insights into mechanisms by which PI3Kδ inhibition promotes antitumor immunity and demonstrate that the mechanism is distinct from that mediated by immune checkpoint blockade.
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Responses to the Selective Bruton's Tyrosine Kinase (BTK) Inhibitor Tirabrutinib (ONO/GS-4059) in Diffuse Large B-cell Lymphoma Cell Lines.Bruton's tyrosine kinase (BTK) is a key regulator of the B-cell receptor signaling pathway, and aberrant B-cell receptor (BCR) signaling has been implicated in the survival of malignant B-cells. However, responses of the diffuse large B-cell lymphoma (DLBCL) to inhibitors of BTK (BTKi) are infrequent, highlighting the need to identify mechanisms of resistance to BTKi as well as predictive biomarkers. We investigated the response to the selective BTKi, tirabrutinib, in a panel of 64 hematopoietic cell lines. Notably, only six cell lines were found to be sensitive. Although activated B-cell type DLBCL cells were most sensitive amongst all cell types studied, sensitivity to BTKi did not correlate with the presence of activating mutations in the BCR pathway. To improve efficacy of tirabrutinib, we investigated combination strategies with 43 drugs inhibiting 34 targets in six DLBCL cell lines. Based on the results, an activated B-cell-like (ABC)-DLBCL cell line, TMD8, was the most sensitive cell line to those combinations, as well as tirabrutinib monotherapy. Furthermore, tirabrutinib in combination with idelalisib, palbociclib, or trametinib was more effective in TMD8 with acquired resistance to tirabrutinib than in the parental cells. These targeted agents might be usefully combined with tirabrutinib in the treatment of ABC-DLBCL.
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The PI3Kδ-Selective Inhibitor Idelalisib Minimally Interferes with Immune Effector Function Mediated by Rituximab or Obinutuzumab and Significantly Augments B Cell Depletion In Vivo.Idelalisib is a highly selective oral inhibitor of PI3Kδ indicated for the treatment of patients with relapsed chronic lymphocytic leukemia in combination with rituximab. Despite additive clinical effects, previous studies have paradoxically demonstrated that targeted therapies potentially negatively affect anti-CD20 mAb effector mechanisms. To address these potential effects, we investigated the impact of PI3Kδ inhibition by idelalisib on the effector mechanisms of rituximab and obinutuzumab. At clinically relevant concentrations, idelalisib minimally influenced rituximab- and obinutuzumab-mediated Ab-dependent cellular cytotoxicity and phagocytosis on human lymphoma cell lines, while maintaining the superiority of obinutuzumab-mediated Ab-dependent cellular cytotoxicity. Consistent with this, idelalisib did not influence obinutuzumab-mediated B cell depletion in whole-blood B cell-depletion assays. Further, idelalisib significantly enhanced obinutuzumab-mediated direct cell death of chronic lymphocytic leukemia cells. In murine systems, in vivo inhibition of PI3Kδ minimally interfered with maximal rituximab- or obinutuzumab-mediated depletion of leukemic targets. In addition, the duration of rituximab- and obinutuzumab-mediated depletion of leukemia cells was extended by combination with PI3Kδ inhibition. Collectively, these data demonstrate that PI3Kδ inhibition does not significantly affect the effector mechanisms induced by rituximab or obinutuzumab and provides an effective in vivo therapeutic combination. Therefore, combinations of obinutuzumab and idelalisib are currently being assessed in clinical studies.
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Synergistic Targeting of the Regulatory and Catalytic Subunits of PI3Kδ in Mature B-cell Malignancies.Aberrant activation of the B-cell receptor (BCR) is implicated in the pathogenesis of mature B-cell tumors, a concept validated in part by the clinical success of inhibitors of the BCR-related kinases BTK (Bruton's tyrosine kinase) and PI3Kδ. These inhibitors have limitations, including the paucity of complete responses, acquired resistance, and toxicity. Here, we examined the mechanism by which the cyclic-AMP/PDE4 signaling axis suppresses PI3K, toward identifying a novel mechanism-based combinatorial strategy to attack BCR-dependency in mature B-cell malignancies. We used and diffuse large B-cell lymphoma (DLBCL) cell lines and primary chronic lymphocytic leukemia (CLL) samples to preclinically evaluate the effects of the combination of the FDA-approved phosphodiesterase 4 (PDE4) inhibitor roflumilast and idelalisib on cell survival and tumor growth. Genetic models of gain- and loss-of-function were used to map multiple signaling intermediaries downstream of the BCR. Roflumilast elevates the intracellular levels of cyclic-AMP and synergizes with idelalisib in suppressing tumor growth and PI3K activity. Mechanistically, we show that roflumilast suppresses PI3K by inhibiting BCR-mediated activation of the P85 regulatory subunit, distinguishing itself from idelalisib, an ATP-competitive inhibitor of the catalytic P110 subunit. Using genetic models, we linked the PDE4-regulated modulation of P85 activation to the oncogenic kinase SYK. These data demonstrate that roflumilast and idelalisib suppress PI3K by distinct mechanisms, explaining the basis for their synergism, and suggest that the repurposing of PDE4 inhibitors to treat BCR-dependent malignancies is warranted. .
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