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

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

  • Bioorg Med Chem Lett. 2015 Sep 1;25(17):3458-63. doi: 10.1016/j.bmcl.2015.07.006.
Xiaoyun Lu 1,  Zhang Zhang 2,  Xiaomei Ren 3,  Xiaofeng Pan 3,  Deping Wang 3,  Xiaoxi Zhuang 3,  Jingfeng Luo 3,  Rongmin Yu 4,  Ke Ding 5
Affiliations

Affiliations

  • 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.
PMID: 26195136 DOI: 10.1016/j.bmcl.2015.07.006
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-10943
    98.08%, BCR-ABL 抑制剂
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