Synthesis and identification of GZD856 as an orally bioavailable Bcr-Abl(T315I) inhibitor overcoming acquired imatinib resistance

Bcr-Abl(T315I) induced drug resistance remains a major challenge to chronic myelogenous leukemia (CML) treatment. Herein, we reported GZD856 as a novel orally bioavailable Bcr-Abl(T315I) inhibitor, which strongly suppressed the kinase activities of both native Bcr-Abl and the T315I mutant with IC(50...

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Detalles Bibliográficos
Autores principales: Lu, Xiaoyun, Zhang, Zhang, Ren, Xiaomei, Wang, Deping, Ding, Ke
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2017
Materias:
Research Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6010122/
https://www.ncbi.nlm.nih.gov/pubmed/28260399
http://dx.doi.org/10.1080/14756366.2016.1250757
Descripción
Sumario:Bcr-Abl(T315I) induced drug resistance remains a major challenge to chronic myelogenous leukemia (CML) treatment. Herein, we reported GZD856 as a novel orally bioavailable Bcr-Abl(T315I) inhibitor, which strongly suppressed the kinase activities of both native Bcr-Abl and the T315I mutant with IC(50) values of 19.9 and 15.4 nM, and potently inhibited proliferation of corresponding K562, Ba/F3(WT) and Ba/F3(T315I) cells with IC(50) 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-Abl(T315I). Thus, GZD856 may serve as a promising lead for the development of Bcr-Abl inhibitors overcoming acquired imatinib resistance.

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