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. Epub 2015 Jul 9.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Proliferation
  • Fusion Proteins, bcr-abl / antagonists & inhibitors*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
  • Models, Molecular
  • Mutation
  • Pyrimidines / chemistry*

Substances

  • Pyrimidines
  • Fusion Proteins, bcr-abl
  • pyrimidine