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Synthesis and identification of GZD856 as an orally bioavailable Bcr-AblT315I inhibitor overcoming acquired imatinib resistance.

ABSTRACT: Bcr-AblT315I induced drug resistance remains a major challenge to chronic myelogenous leukemia (CML) treatment. Herein, we reported GZD856 as a novel orally bioavailable Bcr-AblT315I inhibitor, which strongly suppressed the kinase activities of both native Bcr-Abl and the T315I mutant with IC50 values of 19.9 and 15.4?nM, and potently inhibited proliferation of corresponding K562, Ba/F3WT and Ba/F3T315I cells with IC50 values of 2.2, 0.64 and 10.8?nM. Furthermore, GZD856 potently suppressed tumor growth in mouse bearing xenograft K562 and Ba/F3 cells expressing Bcr-AblT315I. Thus, GZD856 may serve as a promising lead for the development of Bcr-Abl inhibitors overcoming acquired imatinib resistance.

SUBMITTER: Lu X

PROVIDER: S-EPMC6010122 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Synthesis and identification of GZD856 as an orally bioavailable Bcr-AblT315I inhibitor overcoming acquired imatinib resistance.

Lu Xiaoyun X Zhang Zhang Z Ren Xiaomei X Wang Deping D Ding Ke K

Journal of enzyme inhibition and medicinal chemistry 20171201 1

Bcr-AblT315I induced drug resistance remains a major challenge to chronic myelogenous leukemia (CML) treatment. Herein, we reported GZD856 as a novel orally bioavailable Bcr-AblT315I inhibitor, which strongly suppressed the kinase activities of both native Bcr-Abl and the T315I mutant with IC50 values of 19.9 and 15.4 nM, and potently inhibited proliferation of corresponding K562, Ba/F3WT and Ba/F3T315I cells with IC50 values of 2 ...[more]

PMID: 28260399

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