Identification of GZD824 as an Orally Bioavailable Inhibitor That Targets Phosphorylated and Nonphosphorylated Breakpoint Cluster Region鈥揂belson (Bcr-Abl) Kinase and Overcomes Clinically Acquired Muta

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• 作者：Xiaomei Ren ; Xiaofen Pan ; Zhang Zhang ; Deping Wang ; Xiaoyun Lu ; Yupeng Li ; Donghai Wen ; Huoyou Long ; Jinfeng Luo ; Yubing Feng ; Xiaoxi Zhuang ; Fengxiang Zhang ; Jianqi Liu ; Fang Leng ; Xingfen Lang ; Yang Bai ; Miaoqin She ; Zhengchao Tu ; Jingxuan Pan ; Ke Ding
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：February 14, 2013
• 年：2013
• 卷：56
• 期：3
• 页码：879-894
• 全文大小：650K
• 年卷期：v.56,no.3(February 14, 2013)
• ISSN：1520-4804

文摘

Bcr-Abl^T315I mutation-induced imatinib resistance remains a major challenge for clinical management of chronic myelogenous leukemia (CML). Herein, we report GZD824 (10a) as a novel orally bioavailable inhibitor against a broad spectrum of Bcr-Abl mutants including T315I. It tightly bound to Bcr-Abl^WT and Bcr-Abl^T315I with K_d values of 0.32 and 0.71 nM, respectively, and strongly inhibited the kinase functions with nanomolar IC₅₀ values. The compound potently suppressed proliferation of Bcr-Abl-positive K562 and Ku812 human CML cells with IC₅₀ values of 0.2 and 0.13 nM, respectively. It also displayed good oral bioavailability (48.7%), a reasonable half-life (10.6 h), and promising in vivo antitumor efficacy. It induced tumor regression in mouse xenograft tumor models driven by Bcr-Abl^WT or the mutants and significantly improved the survival of mice bearing an allograft leukemia model with Ba/F3 cells harboring Bcr-Abl^T315I. GZD824 represents a promising lead candidate for development of Bcr-Abl inhibitors to overcome acquired imatinib resistance.