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Hybrid Pyrimidine Alkynyls Inhibit the Clinically Resistance Related Bcr-Abl(T315I) Mutant

Hybrid Pyrimidine Alkynyls Inhibit the Clinically Resistance Related Bcr-Abl(T315I) Mutant

Xiaoyun Lu, Zhang Zhang, Xiaomei Ren, Xiaofeng Pan, Deping Wang, Xiaoxi Zhuang, Jingfeng Luo, Rongmin Yu, Ke Ding

Bioorg Med Chem Lett. 2015 Sep 1;25(17):3458-63.

PMID: 26195136

Abstract:

A series of pyrimidine alkynyl derivatives were designed and synthesized as new Bcr-Abl inhibitors by hybriding the structural moieties from GNF-7, ponatinib and nilotinib. One of the most potent compounds 4e strongly suppresses Bcr-Abl(WT) and Bcr-Abl(T315I) kinase with IC50 values of 5.0 and 9.0 nM, and inhibits the proliferation of K562 and murine Ba/F3 cells ectopically expressing Bcr-Abl(T315I) cells with IC50 values of 2 and 50 nM, respectively. It also displays good pharmacokinetics properties with an oral bioavailability of 35.3% and T(1/2) value of 48.7 h, and demonstrates significantly suppression on tumor growth in xenografted mice of K562 and Ba/F3 cells expressing Bcr-Abl(T315I). These inhibitors may serve as lead compounds for further developing new anticancer drugs overcoming the clinically acquired resistance against current Bcr-Abl inhibitors.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP839706079	GNF-7		839706-07-9	Price

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