Search results for: CAL-101 Mechanisms: PI3K-p110-delta-specific inhibitor
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Idelalisib induces apoptosis in the lymphoid tissues and impairs lung function in mice.Idelalisib, an inhibitor of the phosphatidylinositol-3-kinase p110δ subunit (PI3Kδ), is approved for treating lymphoid malignancy. The drug is associated with hematopoietic and pulmonary toxicities, which limit its clinical use. However, the toxicity mechanisms are not completely elucidated. In this study, mice were intraperitoneally injected with idelalisib (40 or 80 µg/g) or dimethyl sulfoxide for five days every week for up to four weeks to evaluate the changes in the thymus, spleen, and pulmonary functions. Idelalisib treatment induced thymic involution, decreased CD4/CD8 T-cell population, and increased CD4/CD8 T-cell population. In the spleen, idelalisib dose dependently decreased the lymphocyte viability and cell count. Idelalisib-treated mice exhibited enhanced cleaved caspase-3 expression in the thymus, spleen, and lung tissues. Idelalisib augmented thoracic and airway resistance and decreased thoracic compliance. Thus, PI3Kδ has physiological roles in T-cell development and airway function. Monitoring drug toxicity is important for developing follow-up compounds that target PI3Kδ signalling.
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Resistance Mechanisms to Targeted Agents in Chronic Lymphocytic Leukemia.Agents that specifically target pathologic mechanisms of survival have now been approved for the treatment of chronic lymphocytic leukemia in both the treatment-naive and relapsed/refractory settings. These 4 agents include the Bruton tyrosine kinase inhibitor ibrutinib, the B-cell leukemia/lymphoma-2 inhibitor venetoclax, and the phosphatidylinositol-3 kinase inhibitors idelalisib and duvelisib. Although clinical outcomes are improved with all of these inhibitors, acquired resistance does occur and leads to progression of disease. Resistance to targeted therapy can occur through direct mutations of the target or through the overexpression of alternative cell survival pathways not affected by the specific inhibitor. Determining which patients will develop resistance, why resistance occurs, how to overcome resistance, and when to test for resistance are all subjects of ongoing research. In this review, we describe the current data relative to the development of resistance to targeted therapies in CLL.
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Minimizing and managing treatment-associated complications in patients with chronic lymphocytic leukemia.: During recent years, therapy in chronic lymphocytic leukemia (CLL) has changed dramatically. The introduction of small molecule inhibitors has shown remarkable clinical efficacy in both previously untreated and relapsed CLL patients. However, these therapies are associated with an increased risk of specific adverse events. Selection of the best therapeutic approach for patients with CLL should be based on an assessment of general condition, comorbidities, and most importantly, the individual risk of serious side effects.: The review presents available data about the occurrence, prophylaxis and management of the most common and clinically most relevant adverse events associated with novel therapy in CLL.: The incorporation of novel drugs, such as B-cell receptor inhibitors and venetoclax, a selective inhibitor of B-cell lymphoma, influences the CLL management paradigm. An individualized approach to CLL is now possible with targeted therapies. The appropriate and optimal use of current therapies requires a precise understanding of their mechanisms of action, efficacy and adverse effect profiles. A fuller understanding of the prophylaxis and management of specific adverse events stemming from CLL therapy could minimize its associated morbidity and mortality. Next-generation agents with improved efficacy and better safety profiles will further advance outcomes for patients with CLL.
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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.
2648 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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