Format

Send to

Choose Destination
Bioorg Med Chem Lett. 2015 Sep 1;25(17):3458-63. doi: 10.1016/j.bmcl.2015.07.006. Epub 2015 Jul 9.

Hybrid pyrimidine alkynyls inhibit the clinically resistance related Bcr-Abl(T315I) mutant.

Author information

1
Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190, Kaiyuan Avenue, Science Park, Guangzhou 510530, China. Electronic address: lu_xiaoyun@gibh.ac.cn.
2
Biotechnological Institute of Chinese Materia Medica and Department of Pharmacology, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China; Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190, Kaiyuan Avenue, Science Park, Guangzhou 510530, China.
3
Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190, Kaiyuan Avenue, Science Park, Guangzhou 510530, China.
4
Biotechnological Institute of Chinese Materia Medica and Department of Pharmacology, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China.
5
Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190, Kaiyuan Avenue, Science Park, Guangzhou 510530, China. Electronic address: ding_ke@gibh.ac.cn.

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.

KEYWORDS:

Bcr-Abl(T315I); Chronic myelogenous leukemia (CML); Clinical resistance; Hybride; Pyrimidine alkynyl

PMID:
26195136
DOI:
10.1016/j.bmcl.2015.07.006
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center