Discovery of 3-(3-(4-(1-Aminocyclobutyl)phenyl)-5-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (ARQ 092): An Orally Bioavailable, Selective, and Potent Allosteric AKT Inhibitor.
The work in this paper describes the optimization of the 3-(3-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine chemical series as potent, selective allosteric inhibitors of AKT kinases, leading to the discovery of ARQ 092 (21a). The cocrystal structure of compound 21a bound to full-length AKT1 confirmed the allosteric mode of inhibition of this chemical class and the role of the cyclobutylamine moiety. Compound 21a demonstrated high enzymatic potency against AKT1, AKT2, and AKT3, as well as potent cellular inhibition of AKT activation and the phosphorylation of the downstream target PRAS40. Compound 21a also served as a potent inhibitor of the AKT1-E17K mutant protein and inhibited tumor growth in a human xenograft mouse model of endometrial adenocarcinoma.
ArQule Inc. , One Wall Street, Burlington, Massachusetts 01803, United States.
Jean-Marc
JM
Lapierre
ArQule Inc. , One Wall Street, Burlington, Massachusetts 01803, United States.
Sudharshan
S
Eathiraj
ArQule Inc. , One Wall Street, Burlington, Massachusetts 01803, United States.
David
D
Vensel
ArQule Inc. , One Wall Street, Burlington, Massachusetts 01803, United States.
Yanbin
Y
Liu
ArQule Inc. , One Wall Street, Burlington, Massachusetts 01803, United States.
Cathy O
CO
Bull
ArQule Inc. , One Wall Street, Burlington, Massachusetts 01803, United States.
Susan
S
Cornell-Kennon
Daiichi Sankyo Co., Shinagawa R&D Center, 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
Shin
S
Iimura
ArQule Inc. , One Wall Street, Burlington, Massachusetts 01803, United States.
Eugene W
EW
Kelleher
ArQule Inc. , One Wall Street, Burlington, Massachusetts 01803, United States.
Darin E
DE
Kizer
ArQule Inc. , One Wall Street, Burlington, Massachusetts 01803, United States.
Steffi
S
Koerner
ArQule Inc. , One Wall Street, Burlington, Massachusetts 01803, United States.
Sapna
S
Makhija
Daiichi Sankyo Co., Shinagawa R&D Center, 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
Akihisa
A
Matsuda
ArQule Inc. , One Wall Street, Burlington, Massachusetts 01803, United States.
Magdi
M
Moussa
ArQule Inc. , One Wall Street, Burlington, Massachusetts 01803, United States.
Nivedita
N
Namdev
ArQule Inc. , One Wall Street, Burlington, Massachusetts 01803, United States.
Ronald E
RE
Savage
ArQule Inc. , One Wall Street, Burlington, Massachusetts 01803, United States.
Jeff
J
Szwaya
ArQule Inc. , One Wall Street, Burlington, Massachusetts 01803, United States.
Erika
E
Volckova
ArQule Inc. , One Wall Street, Burlington, Massachusetts 01803, United States.
Neil
N
Westlund
ArQule Inc. , One Wall Street, Burlington, Massachusetts 01803, United States.
Hui
H
Wu
ArQule Inc. , One Wall Street, Burlington, Massachusetts 01803, United States.
Brian
B
Schwartz
D000284:Administration, Oral; D000494:Allosteric Regulation / Q000187:drug effects; D000631:Aminopyridines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D018269:Carcinoma, Endometrioid / Q000188:drug therapy* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
D000631:Aminopyridines; D000970:Antineoplastic Agents; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; C000608559:Miransertib