Identification of GZD824 as an Orally Bioavailable Inhibitor That Targets Phosphorylated and Nonphosphorylated Breakpoint Cluster Region–Abelson (Bcr-Abl) …

…, Y Feng, X Zhuang, F Zhang, J Liu, F Leng…

Index: Ren, Xiaomei; Pan, Xiaofen; Zhang, Zhang; Wang, Deping; Lu, Xiaoyun; Li, Yupeng; Wen, Donghai; Long, Huoyou; Luo, Jinfeng; Feng, Yubing; Zhuang, Xiaoxi; Zhang, Fengxiang; Liu, Jianqi; Leng, Fang; Lang, Xingfen; Bai, Yang; She, Miaoqin; Tu, Zhengchao; Pan, Jingxuan; Ding, Ke Journal of Medicinal Chemistry, 2013 ,  vol. 56,  # 3  p. 879 - 894

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Citation Number: 21

Abstract

Bcr-AblT315I 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-AblWT and Bcr-AblT315I with K d values of 0.32 and 0.71 nM, respectively, and strongly inhibited the kinase functions with nanomolar IC50 values. The ...