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

Nat Chem Biol. 2014 Dec;10(12):1013-9. doi: 10.1038/nchembio.1681. Epub 2014 Oct 19.

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.

MeSH terms

  • Adenosine Triphosphate / chemistry
  • Adenosine Triphosphate / metabolism
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / pharmacology*
  • Autophagy / drug effects*
  • Autophagy / genetics
  • Catalytic Domain
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Class III Phosphatidylinositol 3-Kinases / antagonists & inhibitors*
  • Class III Phosphatidylinositol 3-Kinases / chemistry
  • Class III Phosphatidylinositol 3-Kinases / genetics
  • Drug Synergism
  • Endosomes / drug effects
  • Endosomes / metabolism
  • Everolimus
  • Gene Expression
  • Humans
  • Kidney / enzymology
  • Kidney / pathology
  • Kinetics
  • Lysosomes / drug effects
  • Lysosomes / metabolism
  • Molecular Docking Simulation
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / pharmacology*
  • Pyridines / chemical synthesis
  • Pyridines / pharmacology*
  • Pyrimidinones / chemical synthesis
  • Pyrimidinones / pharmacology*
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Signal Transduction
  • Sirolimus / analogs & derivatives*
  • Sirolimus / chemical synthesis
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*
  • TOR Serine-Threonine Kinases / chemistry
  • TOR Serine-Threonine Kinases / genetics

Substances

  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Pyridines
  • Pyrimidinones
  • Recombinant Proteins
  • SAR405
  • Adenosine Triphosphate
  • Everolimus
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Class III Phosphatidylinositol 3-Kinases
  • Sirolimus

Associated data

  • PDB/4OYS