1. Discovery of (2S)-8-[(3R)-3-methylmorpholin-4-yl]-1-(3-methyl-2-oxobutyl)-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.
- Author
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Pasquier B, El-Ahmad Y, Filoche-Rommé B, Dureuil C, Fassy F, Abecassis PY, Mathieu M, Bertrand T, Benard T, Barrière C, El Batti S, Letallec JP, Sonnefraud V, Brollo M, Delbarre L, Loyau V, Pilorge F, Bertin L, Richepin P, Arigon J, Labrosse JR, Clément J, Durand F, Combet R, Perraut P, Leroy V, Gay F, Lefrançois D, Bretin F, Marquette JP, Michot N, Caron A, Castell C, Schio L, McCort G, Goulaouic H, Garcia-Echeverria C, and Ronan B
- Subjects
- Amino Acid Sequence, Animals, Antineoplastic Agents chemistry, Antineoplastic Agents metabolism, Area Under Curve, Bridged Bicyclo Compounds, Heterocyclic chemistry, Bridged Bicyclo Compounds, Heterocyclic pharmacokinetics, Caco-2 Cells, Cell Line, Tumor, Class III Phosphatidylinositol 3-Kinases chemistry, Class III Phosphatidylinositol 3-Kinases metabolism, Crystallography, X-Ray, Drug Discovery, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacokinetics, HeLa Cells, Humans, Male, Mice, SCID, Models, Chemical, Models, Molecular, Molecular Sequence Data, Molecular Structure, Neoplasms pathology, Protein Binding, Protein Structure, Tertiary, Pyrimidinones chemistry, Pyrimidinones pharmacokinetics, Rats, Sprague-Dawley, Sequence Homology, Amino Acid, Thermodynamics, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacology, Bridged Bicyclo Compounds, Heterocyclic pharmacology, Class III Phosphatidylinositol 3-Kinases antagonists & inhibitors, Enzyme Inhibitors pharmacology, Neoplasms drug therapy, Pyrimidinones pharmacology
- Abstract
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 tetrahydropyrimidopyrimidinone derivatives. Starting with hit compound 1a, 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 illustrates 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.
- Published
- 2015
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