9-(Arenethenyl)purines as Dual Src/Abl Kinase Inhibitors Targeting the Inactive Conformation: Design, Synthesis, and Biological Evaluation

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• 作者：Wei-Sheng Huang ; Xiaotian Zhu ; Yihan Wang ; Mohammad Azam ; David Wen ; Raji Sundaramoorthi ; R. Mathew Thomas ; Shuangying Liu ; Geetha Banda ; Scott P. Lentini ; Sasmita Das ; Qihong Xu ; Jeff Keats ; Frank Wa
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：August 13, 2009
• 年：2009
• 卷：52
• 期：15
• 页码：4743-4756
• 全文大小：1139K
• 年卷期：v.52,no.15(August 13, 2009)
• ISSN：1520-4804

文摘

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.