1421685-07-5Relevant articles and documents
Identification of GZD824 as an orally bioavailable inhibitor that targets phosphorylated and nonphosphorylated breakpoint cluster region-Abelson (Bcr-Abl) kinase and overcomes clinically acquired mutation-induced resistance against imatinib
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
, p. 879 - 894 (2013/03/28)
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 Kd 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 IC 50 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-AblWT or the mutants and significantly improved the survival of mice bearing an allograft leukemia model with Ba/F3 cells harboring Bcr-AblT315I. GZD824 represents a promising lead candidate for development of Bcr-Abl inhibitors to overcome acquired imatinib resistance.
