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Title: Discovery of 3-(3-(4-(1-Aminocyclobutyl)phenyl)-5-phenyl-3 H -imidazo[4,5- b ]pyridin-2-yl)pyridin-2-amine (ARQ 092): An Orally Bioavailable, Selective, and Potent Allosteric AKT Inhibitor

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.

Authors:
; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Brookhaven National Lab. (BNL), Upton, NY (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
OSTI Identifier:
1354334
Report Number(s):
BNL-112850-2016-JA
Journal ID: ISSN 0022-2623
DOE Contract Number:  
SC00112704
Resource Type:
Journal Article
Journal Name:
Journal of Medicinal Chemistry
Additional Journal Information:
Journal Volume: 59; Journal Issue: 13; Journal ID: ISSN 0022-2623
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
English
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; 60 APPLIED LIFE SCIENCES

Citation Formats

Lapierre, Jean-Marc, Eathiraj, Sudharshan, Vensel, David, Liu, Yanbin, Bull, Cathy O., Cornell-Kennon, Susan, Iimura, Shin, Kelleher, Eugene W., Kizer, Darin E., Koerner, Steffi, Makhija, Sapna, Matsuda, Akihisa, Moussa, Magdi, Namdev, Nivedita, Savage, Ronald E., Szwaya, Jeff, Volckova, Erika, Westlund, Neil, Wu, Hui, and Schwartz, Brian. Discovery of 3-(3-(4-(1-Aminocyclobutyl)phenyl)-5-phenyl-3 H -imidazo[4,5- b ]pyridin-2-yl)pyridin-2-amine (ARQ 092): An Orally Bioavailable, Selective, and Potent Allosteric AKT Inhibitor. United States: N. p., 2016. Web. doi:10.1021/acs.jmedchem.6b00619.
Lapierre, Jean-Marc, Eathiraj, Sudharshan, Vensel, David, Liu, Yanbin, Bull, Cathy O., Cornell-Kennon, Susan, Iimura, Shin, Kelleher, Eugene W., Kizer, Darin E., Koerner, Steffi, Makhija, Sapna, Matsuda, Akihisa, Moussa, Magdi, Namdev, Nivedita, Savage, Ronald E., Szwaya, Jeff, Volckova, Erika, Westlund, Neil, Wu, Hui, & Schwartz, Brian. Discovery of 3-(3-(4-(1-Aminocyclobutyl)phenyl)-5-phenyl-3 H -imidazo[4,5- b ]pyridin-2-yl)pyridin-2-amine (ARQ 092): An Orally Bioavailable, Selective, and Potent Allosteric AKT Inhibitor. United States. doi:10.1021/acs.jmedchem.6b00619.
Lapierre, Jean-Marc, Eathiraj, Sudharshan, Vensel, David, Liu, Yanbin, Bull, Cathy O., Cornell-Kennon, Susan, Iimura, Shin, Kelleher, Eugene W., Kizer, Darin E., Koerner, Steffi, Makhija, Sapna, Matsuda, Akihisa, Moussa, Magdi, Namdev, Nivedita, Savage, Ronald E., Szwaya, Jeff, Volckova, Erika, Westlund, Neil, Wu, Hui, and Schwartz, Brian. Wed . "Discovery of 3-(3-(4-(1-Aminocyclobutyl)phenyl)-5-phenyl-3 H -imidazo[4,5- b ]pyridin-2-yl)pyridin-2-amine (ARQ 092): An Orally Bioavailable, Selective, and Potent Allosteric AKT Inhibitor". United States. doi:10.1021/acs.jmedchem.6b00619.
@article{osti_1354334,
title = {Discovery of 3-(3-(4-(1-Aminocyclobutyl)phenyl)-5-phenyl-3 H -imidazo[4,5- b ]pyridin-2-yl)pyridin-2-amine (ARQ 092): An Orally Bioavailable, Selective, and Potent Allosteric AKT Inhibitor},
author = {Lapierre, Jean-Marc and Eathiraj, Sudharshan and Vensel, David and Liu, Yanbin and Bull, Cathy O. and Cornell-Kennon, Susan and Iimura, Shin and Kelleher, Eugene W. and Kizer, Darin E. and Koerner, Steffi and Makhija, Sapna and Matsuda, Akihisa and Moussa, Magdi and Namdev, Nivedita and Savage, Ronald E. and Szwaya, Jeff and Volckova, Erika and Westlund, Neil and Wu, Hui and Schwartz, Brian},
abstractNote = {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.},
doi = {10.1021/acs.jmedchem.6b00619},
journal = {Journal of Medicinal Chemistry},
issn = {0022-2623},
number = 13,
volume = 59,
place = {United States},
year = {2016},
month = {6}
}