title: A highly potent and selective Vps34 inhibitor alters vesicle trafficking and autophagy.
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.
authors.affiliation: Oncology Drug Discovery, Sanofi, Vitry Sur Seine, France.
authors.forename: Baptiste
authors.initials: B
authors.lastname: Ronan
authors.affiliation: Oncology Drug Discovery, Sanofi, Vitry Sur Seine, France.
authors.forename: Odile
authors.initials: O
authors.lastname: Flamand
authors.affiliation: Oncology Drug Discovery, Sanofi, Vitry Sur Seine, France.
authors.forename: Lionel
authors.initials: L
authors.lastname: Vescovi
authors.affiliation: Oncology Drug Discovery, Sanofi, Vitry Sur Seine, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Dureuil
authors.affiliation: Oncology Drug Discovery, Sanofi, Vitry Sur Seine, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Durand
authors.affiliation: Oncology Drug Discovery, Sanofi, Vitry Sur Seine, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Fassy
authors.affiliation: Oncology Drug Discovery, Sanofi, Vitry Sur Seine, France.
authors.forename: Marie-France
authors.initials: MF
authors.lastname: Bachelot
authors.affiliation: Oncology Drug Discovery, Sanofi, Vitry Sur Seine, France.
authors.forename: Annabelle
authors.initials: A
authors.lastname: Lamberton
authors.affiliation: Structure, Design and Informatics, Sanofi, Vitry Sur Seine, France..
authors.forename: Magali
authors.initials: M
authors.lastname: Mathieu
authors.affiliation: Structure, Design and Informatics, Sanofi, Vitry Sur Seine, France..
authors.forename: Thomas
authors.initials: T
authors.lastname: Bertrand
authors.affiliation: Structure, Design and Informatics, Sanofi, Vitry Sur Seine, France..
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Marquette
authors.affiliation: Oncology Drug Discovery, Sanofi, Vitry Sur Seine, France.
authors.forename: Youssef
authors.initials: Y
authors.lastname: El-Ahmad
authors.affiliation: Oncology Drug Discovery, Sanofi, Vitry Sur Seine, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Filoche-Romme
authors.affiliation: Oncology Drug Discovery, Sanofi, Vitry Sur Seine, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Schio
authors.affiliation: Oncology Drug Discovery, Sanofi, Vitry Sur Seine, France.
authors.forename: Carlos
authors.initials: C
authors.lastname: Garcia-Echeverria
authors.affiliation: Oncology Drug Discovery, Sanofi, Vitry Sur Seine, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Goulaouic
authors.affiliation: Oncology Drug Discovery, Sanofi, Vitry Sur Seine, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Pasquier
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects* / Q000235:genetics; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D058546:Class III Phosphatidylinositol 3-Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D004357:Drug Synergism; D011992:Endosomes / Q000187:drug effects / Q000378:metabolism; D000068338:Everolimus; D015870:Gene Expression; D006801:Humans; D007668:Kidney / Q000201:enzymology / Q000473:pathology; D007700:Kinetics; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D062105:Molecular Docking Simulation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis / Q000494:pharmacology*; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics; D015398:Signal Transduction; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011744:Pyrimidinones; D011994:Recombinant Proteins; C000594652:SAR405; D000255:Adenosine Triphosphate; D000068338:Everolimus; C546842:MTOR protein, human; D058546:Class III Phosphatidylinositol 3-Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus