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

Jean-Marc Lapierre; Sudharshan Eathiraj; David Vensel; Yanbin Liu; Cathy O Bull; Susan Cornell-Kennon; Shin Iimura; Eugene W Kelleher; Darin E Kizer; Steffi Koerner; Sapna Makhija; Akihisa Matsuda; Magdi Moussa; Nivedita Namdev; Ronald E Savage; Jeff Szwaya; Erika Volckova; Neil Westlund; Hui Wu; Brian Schwartz

doi:10.1021/acs.jmedchem.6b00619

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

J Med Chem. 2016 Jul 14;59(13):6455-69. doi: 10.1021/acs.jmedchem.6b00619. Epub 2016 Jun 29.

Authors

Jean-Marc Lapierre¹, Sudharshan Eathiraj¹, David Vensel¹, Yanbin Liu¹, Cathy O Bull¹, Susan Cornell-Kennon¹, Shin Iimura², Eugene W Kelleher¹, Darin E Kizer¹, Steffi Koerner¹, Sapna Makhija¹, Akihisa Matsuda², Magdi Moussa¹, Nivedita Namdev¹, Ronald E Savage¹, Jeff Szwaya¹, Erika Volckova¹, Neil Westlund¹, Hui Wu¹, Brian Schwartz¹

Affiliations

¹ ArQule Inc. , One Wall Street, Burlington, Massachusetts 01803, United States.
² Daiichi Sankyo Co., Shinagawa R&D Center, 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.

PMID: 27305487
DOI: 10.1021/acs.jmedchem.6b00619

Abstract

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.

MeSH terms

Administration, Oral
Allosteric Regulation / drug effects
Aminopyridines / administration & dosage
Aminopyridines / chemistry
Aminopyridines / pharmacology*
Animals
Antineoplastic Agents / administration & dosage
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Carcinoma, Endometrioid / drug therapy*
Carcinoma, Endometrioid / pathology
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Discovery*
Drug Screening Assays, Antitumor
Endometrial Neoplasms / drug therapy*
Endometrial Neoplasms / pathology
Female
Humans
Imidazoles / administration & dosage
Imidazoles / chemistry
Imidazoles / pharmacology*
Mice
Molecular Structure
Neoplasms, Experimental / drug therapy
Neoplasms, Experimental / pathology
Protein Kinase Inhibitors / administration & dosage
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
Proto-Oncogene Proteins c-akt / genetics
Proto-Oncogene Proteins c-akt / metabolism
Structure-Activity Relationship

Substances

Aminopyridines
Antineoplastic Agents
Imidazoles
Protein Kinase Inhibitors
Proto-Oncogene Proteins c-akt
Miransertib

Grants and funding

P41 GM111244/GM/NIGMS NIH HHS/United States