Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 56, Issue 3, Pages 879-894Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm301581y
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Funding
- National Basic Research Program of China [2010CB529706]
- Major Projects in National Science and Technology Creation of major new drugs [2013ZX0910204]
- National Natural Science Foundation [21072192, 21102146]
- key Project on Innovative Drug of Guangdong province [2011A080501013]
- Key Project on Innovative Drug of Guangzhou City [2009Z1-E911, 2010J-E551, 12C34061592]
- Chinese Academy of Sciences (CAS)
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Bcr-Abl(T315)I 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 IC50 values. The compound potently suppressed proliferation of Bcr-Abl-positive K562 and Ku812 human CML cells with IC50 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.
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