9-(Arenethenyl)purines as Dual Src/Abl Kinase Inhibitors Targeting the Inactive Conformation: Design, Synthesis, and Biological Evaluation
| Autor: | Jeff Keats, Marc I Broudy, John Iuliucci, Scott Wardwell, Karin Russian, Sasmita Das, Yaoyu Ning, Scott Paul Lentini, Yihan Wang, David Wen, William C. Shakespeare, Joseph Snodgrass, Tomi K. Sawyer, David C. Dalgarno, R. Mathew Thomas, Xiaotian Zhu, Mohammad Azam, Shuangying Liu, George Q. Daley, Wei-Sheng Huang, Raji Sundaramoorthi, Tim Clackson, Geetha Banda, Qihong Xu, Frank Wang |
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| Rok vydání: | 2009 |
| Předmět: |
Protein Conformation
Pharmacology Mice Structure-Activity Relationship In vivo hemic and lymphatic diseases Drug Discovery Animals Humans Proto-Oncogene Proteins c-abl Protein Kinase Inhibitors ABL biology Kinase Chemistry Wild type Myeloid leukemia Rats src-Family Kinases Purines Enzyme inhibitor Drug Design NIH 3T3 Cells biology.protein Molecular Medicine Female K562 Cells Proto-oncogene tyrosine-protein kinase Src K562 cells |
| Zdroj: | Journal of Medicinal Chemistry. 52:4743-4756 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | A novel series of potent dual Src/Abl kinase inhibitors based on a 9-(arenethenyl)purine core has been identified. Unlike traditional dual Src/Abl inhibitors targeting the active enzyme conformation, these inhibitors bind to the inactive, DFG-out conformation of both kinases. Extensive SAR studies led to the discovery of potent and orally bioavailable inhibitors, some of which demonstrated in vivo efficacy. Once-daily oral administration of inhibitor 9i (AP24226) significantly prolonged the survival of mice injected intravenously with wild type Bcr-Abl expressing Ba/F3 cells at a dose of 10 mg/kg. In a separate model, oral administration of 9i to mice bearing subcutaneous xenografts of Src Y527F expressing NIH 3T3 cells elicited dose-dependent tumor shrinkage with complete tumor regression observed at the highest dose. Notably, several inhibitors (e.g., 14a, AP24163) exhibited modest cellular potency (IC50 = 300-400 nM) against the Bcr-Abl mutant T315I, a variant resistant to all currently marketed therapies for chronic myeloid leukemia. |
| Databáze: | OpenAIRE |
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