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.
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.
Oncology Drug Discovery, ‡Drug Disposition and Safety, §Structure Design Informatics and Structural Biology, ∥Pharmaceutical Sciences Operations, ⊥Protein Production, and #Global Biotherapeutic, Sanofi , 13 Quai Jules Guesde, 94403 Vitry-sur-Seine, France.
Benoit
B
Pasquier
Youssef
Y
El-Ahmad
Bruno
B
Filoche-Rommé
Christine
C
Dureuil
Florence
F
Fassy
Pierre-Yves
PY
Abecassis
Magali
M
Mathieu
Thomas
T
Bertrand
Tsiala
T
Benard
Cédric
C
Barrière
Samira
S
El Batti
Jean-Philippe
JP
Letallec
Véronique
V
Sonnefraud
Maurice
M
Brollo
Laurence
L
Delbarre
Véronique
V
Loyau
Fabienne
F
Pilorge
Luc
L
Bertin
Patrick
P
Richepin
Jérôme
J
Arigon
Jean-Robert
JR
Labrosse
Jacques
J
Clément
Florence
F
Durand
Romain
R
Combet
Pierre
P
Perraut
Vincent
V
Leroy
Frédéric
F
Gay
Dominique
D
Lefrançois
François
F
Bretin
Jean-Pierre
JP
Marquette
Nadine
N
Michot
Anne
A
Caron
Christelle
C
Castell
Laurent
L
Schio
Gary
G
McCort
Hélène
H
Goulaouic
Carlos
C
Garcia-Echeverria
Baptiste
B
Ronan
D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D019540:Area Under Curve; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D058546:Class III Phosphatidylinositol 3-Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D008297:Male; D016513:Mice, SCID; D008956:Models, Chemical; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011744:Pyrimidinones / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D017386:Sequence Homology, Amino Acid; D013816:Thermodynamics; D023041:Xenograft Model Antitumor Assays
C000597232:8-(3-methylmorpholin-4-yl)-1-(3-methyl-2-oxobutyl)-2-(trifluoromethyl)-3,4-dihydro-2H-pyrimido(1,2-a)pyrimidin-6-one; D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004791:Enzyme Inhibitors; D011744:Pyrimidinones; D058546:Class III Phosphatidylinositol 3-Kinases