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

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

Research output: Contribution to journalArticlepeer-review

49 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)879-894
Number of pages16
JournalJournal of Medicinal Chemistry
Volume56
Issue number3
DOIs
StatePublished - Feb 14 2013
Externally publishedYes

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