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.

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.

• Authors: 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
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 56 Issue 3 Pg. 879-94 (Feb 14 2013) ISSN: 1520-4804 [Electronic] United States
• PMID: 23301703 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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