4OYS

CRYSTAL STRUCTURE OF VPS34 IN COMPLEX WITH SAR405.

Summary for 4OYS

• Entry DOI: 10.2210/pdb4oys/pdb
• Descriptor: Phosphatidylinositol 3-kinase catalytic subunit type 3, SULFATE ION, (8S)-9-[(5-chloranylpyridin-3-yl)methyl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(trifluoromethyl)-6,7,8,9a-tetrahydro-3H-pyrimido[1,2-a]pyrimidin-4-one, ... (4 entities in total)
• Functional Keywords: lipid kinase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 69427.51

Authors

Mathieu, M.,Marquette, J.p. (deposition date: 2014-02-13, release date: 2014-10-22, Last modification date: 2024-03-27)

Primary citation

Ronan, B.,Flamand, O.,Vescovi, L.,Dureuil, C.,Durand, L.,Fassy, F.,Bachelot, M.F.,Lamberton, A.,Mathieu, M.,Bertrand, T.,Marquette, J.P.,El-Ahmad, Y.,Filoche-Romme, B.,Schio, L.,Garcia-Echeverria, C.,Goulaouic, H.,Pasquier, B.
A highly potent and selective Vps34 inhibitor alters vesicle trafficking and autophagy.
Nat.Chem.Biol., 10:1013-1019, 2014

PubMed 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.

PubMed: 25326666
DOI: 10.1038/nchembio.1681

Experimental method

X-RAY DIFFRACTION (2.9 Å)