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

doi:10.1021/jm301581y

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

J Med Chem. 2013 Feb 14;56(3):879-94. doi: 10.1021/jm301581y. Epub 2013 Jan 28.

Affiliation

¹ Institute of Chemical Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, #190 Kaiyuan Avenue, Guangzhou 510530, China.

PMID: 23301703
DOI: 10.1021/jm301581y

Abstract

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 IC(50) 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-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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Administration, Oral
Animals
Antineoplastic Agents / administration & dosage
Antineoplastic Agents / pharmacokinetics
Antineoplastic Agents / pharmacology*
Benzamides / administration & dosage
Benzamides / pharmacokinetics
Benzamides / pharmacology*
Biological Availability
Cell Line, Tumor
Drug Resistance, Neoplasm / genetics*
Fusion Proteins, bcr-abl / antagonists & inhibitors*
Fusion Proteins, bcr-abl / metabolism
Humans
Imatinib Mesylate
Magnetic Resonance Spectroscopy
Models, Molecular
Mutation*
Phosphorylation
Piperazines / pharmacology*
Protein Kinase Inhibitors / administration & dosage
Protein Kinase Inhibitors / pharmacokinetics
Protein Kinase Inhibitors / pharmacology*
Protein-Tyrosine Kinases / antagonists & inhibitors*
Protein-Tyrosine Kinases / metabolism
Pyrazoles / administration & dosage
Pyrazoles / pharmacokinetics
Pyrazoles / pharmacology*
Pyrimidines / pharmacology*
Spectrometry, Mass, Electrospray Ionization

Substances

Antineoplastic Agents
Benzamides
Piperazines
Protein Kinase Inhibitors
Pyrazoles
Pyrimidines
Imatinib Mesylate
Protein-Tyrosine Kinases
Fusion Proteins, bcr-abl
olverembatinib