Abstract
SAR405 is a first-in-class VPS34 inhibitor that disrupts vesicle trafficking and blocks autophagy.
Major finding: SAR405 is a first-in-class VPS34 inhibitor that disrupts vesicle trafficking and blocks autophagy.
Clinical relevance: SAR405 synergizes with the mTOR inhibitor everolimus to suppress cancer cell growth.
Impact: Specific inhibition of VPS34 may shed light on mechanisms regulating autophagy and its role in cancer.
Autophagy can promote cancer cell survival in certain contexts by recycling nutrients from damaged proteins and organelles and is considered an attractive therapeutic target. Ronan and colleagues screened a collection of approximately 250,000 compounds for inhibitors of autophagy and identified a series of compounds with activity against the lipid kinase VPS34, a class III PI3K isoform that promotes autophagosome formation and regulates vesicle trafficking. Lead optimization led to the development of SAR405, a highly potent VPS34 inhibitor that did not have activity against other protein and lipid kinases. Structural analysis of VPS34 in complex with SAR405 suggested that SAR405 engaged in interactions with features of the VPS34 ATP binding cleft that are not shared with class I and II PI3Ks or the related kinase mTOR, thus providing an explanation for the exquisite selectivity of SAR405 for VPS34. SAR405 treatment disrupted vesicle trafficking from late endosomes to lysosomes and inhibited autophagosome formation in human cancer cell lines in a dose-dependent manner. SAR405 also blocked starvation-induced autophagy as well as autophagy induced as a potential survival mechanism in response to mTOR inhibition. This finding prompted the authors to investigate whether SAR405 would increase the anticancer activity of the mTOR inhibitor everolimus, which has been approved by the FDA for treatment of renal cell carcinoma and several other cancers. Indeed, SAR405 and everolimus synergistically reduced the proliferation of two renal cancer cell lines in vitro, providing a rationale for further exploration of combined VPS34 and mTOR inhibition in renal cell carcinoma. The development of a highly potent and selective VPS34 inhibitor provides a new targeted strategy for inhibiting autophagy in cancer cells and may lead to a better understanding of the mechanisms that regulate autophagy.
