| Structural highlights
Function
[PK3C3_HUMAN] Catalytic subunit of the PI3K complex that mediates formation of phosphatidylinositol 3-phosphate which plays a key role in initiation and maturation of autophagosomes. Involved in the transport of lysosomal enzyme precursors to lysosomes. Required for the abcission step in cytokinesis. Required for transport from early to late endosomes.[1] [2] [3]
Publication Abstract from PubMed
Vps34 (the human class III phosphoinositide 3-kinase) is a lipid kinase involved in vesicle trafficking and autophagy and therefore constitutes an interesting target for cancer treatment. Because of the lack of specific Vps34 kinase inhibitors, we aimed to identify such compounds to further validate the role of this lipid kinase in cancer maintenance and progression. Herein, we report the discovery of a series of tetrahydropyrimido-pyrimidinone derivatives. Starting with hit compound 1, medicinal chemistry optimization led to compound 31. This molecule displays potent activity, an exquisite selectivity for Vps34 with excellent properties. The X-ray crystal structure of compound 31 in human Vps34 illustrated how the unique molecular features of the morpholine synthon bestows selectivity against class I PI3Ks. This molecule exhibits suitable in vivo mouse PK parameters and induces a sustained inhibition of Vps34 upon acute administration. Compound 31 constitutes an optimized Vps34 inhibitor that could be used to investigate human cancer biology.
Discovery of (2S)-8-[(3R)-3-Methylmorpholin-4-yl]-1-(3-methyl-2-oxo-butyl)-2-(trifluoromethyl) -3,4-dihydro-2H-pyrimido[1,2-a]pyrimidin-6-one: a Novel Potent and Selective Inhibitor of Vps34 for the Treatment of Solid Tumors.,Pasquier B, El-Ahmad Y, Filoche-Romme B, Dureuil-Sizaire C, Fassy F, Abecassis PY, Mathieu M, Bertrand T, Benard T, Barriere C, El Batti S, Letallec JP, Sonnefraud V, Brollo M, Delbarre L, Loyau V, Pilorge F, Bertin L, Richepin P, Arigon J, Labrosse JR, Clement J, Durand F, Combet R, Perraut P, Leroy V, Gay F, Lefrancois D, Bretin F, Marquette JP, Michot N, Caron A, Castell C, Schio L, McCort G, Goulaouic H, Garcia-Echeverria C, Ronan BP J Med Chem. 2014 Nov 17. PMID:25402320[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Volinia S, Dhand R, Vanhaesebroeck B, MacDougall LK, Stein R, Zvelebil MJ, Domin J, Panaretou C, Waterfield MD. A human phosphatidylinositol 3-kinase complex related to the yeast Vps34p-Vps15p protein sorting system. EMBO J. 1995 Jul 17;14(14):3339-48. PMID:7628435
- ↑ Stein MP, Feng Y, Cooper KL, Welford AM, Wandinger-Ness A. Human VPS34 and p150 are Rab7 interacting partners. Traffic. 2003 Nov;4(11):754-71. PMID:14617358
- ↑ Sagona AP, Nezis IP, Pedersen NM, Liestol K, Poulton J, Rusten TE, Skotheim RI, Raiborg C, Stenmark H. PtdIns(3)P controls cytokinesis through KIF13A-mediated recruitment of FYVE-CENT to the midbody. Nat Cell Biol. 2010 Apr;12(4):362-71. doi: 10.1038/ncb2036. Epub 2010 Mar 7. PMID:20208530 doi:http://dx.doi.org/10.1038/ncb2036
- ↑ Pasquier B, El-Ahmad Y, Filoche-Romme B, Dureuil-Sizaire C, Fassy F, Abecassis PY, Mathieu M, Bertrand T, Benard T, Barriere C, El Batti S, Letallec JP, Sonnefraud V, Brollo M, Delbarre L, Loyau V, Pilorge F, Bertin L, Richepin P, Arigon J, Labrosse JR, Clement J, Durand F, Combet R, Perraut P, Leroy V, Gay F, Lefrancois D, Bretin F, Marquette JP, Michot N, Caron A, Castell C, Schio L, McCort G, Goulaouic H, Garcia-Echeverria C, Ronan BP. Discovery of (2S)-8-[(3R)-3-Methylmorpholin-4-yl]-1-(3-methyl-2-oxo-butyl)-2-(trifluoromethyl) -3,4-dihydro-2H-pyrimido[1,2-a]pyrimidin-6-one: a Novel Potent and Selective Inhibitor of Vps34 for the Treatment of Solid Tumors. J Med Chem. 2014 Nov 17. PMID:25402320 doi:http://dx.doi.org/10.1021/jm5013352
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