Abstract
Vps34 is a phosphoinositide 3-kinase (PI3K) class III isoform that has attracted major attention over the recent years because of its role in autophagy. Herein we describe the biological characterization of SAR405, which is a low-molecular-mass kinase inhibitor of Vps34 (KD 1.5 nM). This compound has an exquisite protein and lipid kinase selectivity profile that is explained by its unique binding mode and molecular interactions within the ATP binding cleft of human Vps34. To the best of our knowledge, this is the first potent and specific Vps34 inhibitor described so far. Our results demonstrate that inhibition of Vps34 kinase activity by SAR405 affects both late endosome-lysosome compartments and prevents autophagy. Moreover, we show that the concomitant inhibition of Vps34 and mTOR, with SAR405 and the US Food and Drug Administration–approved mTOR inhibitor everolimus, results in synergistic antiproliferative activity in renal tumor cell lines, indicating a potential clinical application in cancer.
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Acknowledgements
We thank C. Capdevila, N. Michot, S. Plantard, C. Valtre, M. Lowinski, A. Rak, C. Castell, V. Bazin, C. Delorme, H. Robbe, J.-P. Ridoux, A. Casse, F. Windenberger, A.-C. Kerangueven, V. Onado, S. El Batti, J.-P. Letallec, V. Sonnefraud, F. Gay, M. Brollo, L. Delbarre, V. Loyau, P. Richepin, L. Bertin, F. Pilorge and G. McCort for their valuable input and discussion.
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O.F., L.V., L.D. and C.D. performed all the cellular assays; M.-F.B., A.L. and F.F. performed the biochemical assays; J.-P.M., M.M. and T.B. performed the co-crystallization and structural analysis; B.R., Y.E.-A., B.F.-R. designed and contributed to the synthesis of chemical compounds; L.S., C.G.-E. and H.G. contributed to discussions and revised the manuscript; B.P. designed the biological experiments, directed the project and wrote the manuscript.
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The authors have competing interests. All of the authors are employees of Sanofi, and all are or have been shareholders of Sanofi.
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Supplementary Results, Supplementary Figures 1–21 and Supplementary Tables 1 and 2. (PDF 2606 kb)
Supplementary Data Set
Kinase profiling of SAR405 (PDF 1340 kb)
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Ronan, B., Flamand, O., Vescovi, L. et al. A highly potent and selective Vps34 inhibitor alters vesicle trafficking and autophagy. Nat Chem Biol 10, 1013–1019 (2014). https://doi.org/10.1038/nchembio.1681
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DOI: https://doi.org/10.1038/nchembio.1681
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