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
| Autor: | Jean-Marc Lapierre, Cathy O. Bull, Ronald E. Savage, Sudharshan Eathiraj, David Vensel, Sapna Makhija, Eugene Kelleher, Neil Westlund, Jeff Szwaya, Yanbin Liu, Steffi Koerner, Magdi Moussa, Susan Cornell-Kennon, Akihisa Matsuda, Darin Kizer, Nivedita Namdev, Hui Wu, Shin Iimura, Brian Schwartz, Erika Volckova |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Stereochemistry Allosteric regulation Administration Oral Aminopyridines AKT1 Antineoplastic Agents AKT2 Mice Structure-Activity Relationship 03 medical and health sciences 0302 clinical medicine Allosteric Regulation Drug Discovery Animals Humans Moiety Protein Kinase Inhibitors Protein kinase B Cell Proliferation chemistry.chemical_classification Dose-Response Relationship Drug Molecular Structure Kinase Imidazoles Neoplasms Experimental Endometrial Neoplasms 030104 developmental biology Enzyme chemistry 030220 oncology & carcinogenesis embryonic structures Molecular Medicine Phosphorylation Female Drug Screening Assays Antitumor Carcinoma Endometrioid Proto-Oncogene Proteins c-akt |
| Zdroj: | Journal of Medicinal Chemistry. 59:6455-6469 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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