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A highly potent and selective Vps34 inhibitor alters vesicle trafficking and autophagy.

Nature chemical biology (2014-10-20)
Baptiste Ronan, Odile Flamand, Lionel Vescovi, Christine Dureuil, Laurence Durand, Florence Fassy, Marie-France Bachelot, Annabelle Lamberton, Magali Mathieu, Thomas Bertrand, Jean-Pierre Marquette, Youssef El-Ahmad, Bruno Filoche-Romme, Laurent Schio, Carlos Garcia-Echeverria, Hélène Goulaouic, Benoit Pasquier
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.

MATERIALS
Product Number
Brand
Product Description

Supelco
Rapamycin, VETRANAL®, analytical standard
Sigma-Aldrich
Rapamycin from Streptomyces hygroscopicus, ≥95% (HPLC), powder