SAR405, a PIK3C3/Vps34 inhibitor that prevents autophagy and synergizes with MTOR inhibition in tumor cells

摘要: Autophagy plays an important role in cancer and it has been suggested that functions not only as a tumor suppressor pathway to prevent initiation, but also prosurvival helps cells endure metabolic stress resist death triggered by chemotherapeutic agents. We recently described the discovery of inhibitors PIK3C3/Vps34 (phosphatidylinositol 3-kinase, catalytic subunit type 3), lipid kinase component class III phosphatidylinositol 3-kinase (PtdIns3K). This PtdIns3K isoform attracted significant attention recent years because its autophagy. Following chemical optimization we identified SAR405, low molecular mass inhibitor PIK3C3, highly potent selective with regard other protein kinases. demonstrated inhibiting activity PIK3C3 disrupts vesicle trafficking from late endosomes lysosomes. SAR405 treatment inhibits autophagy induced either starvation or MTOR (mechanistic target rapamycin) inhibition. Finally our results show combining everolimus, FDA-approved inhibitor, synergy on reduction cell proliferation using renal cells. result indicates potential therapeutic application for cancer.