Activity of the potent dual Abl/Src tyrosine kinase inhibitor FB2 against Bcr-Abl positive cell lines in vitro and in vivo

Leuk Res. 2011 Feb;35(2):237-42. doi: 10.1016/j.leukres.2010.07.041. Epub 2010 Aug 23.

Abstract

We have previously shown the inhibition of the small-molecule inhibitor FB2 on imatinib-sensitive and resistance CML cell lines with the wild-type Bcr-Abl fusion gene. Here we report the potent and selective antiproliferation on FB2 on transfected Ba/F3 p210 cell lines expressing various isoforms of Bcr-Abl (wild-type, Y253F, T315I). FB2 which orients Bcr-Abl and Src kinase activities, is shown to override imatinib-resistance CML involving Y253F mutation in the Abl kinase domain of the fusion protein except T315I in vivo and in vitro. Thus, we present FB2 that displays potency toward Bcr-Abl and Src as the molecular target, and which could potentially be used to override drug resistance in CML.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Separation
  • Drug Resistance, Neoplasm / genetics
  • Female
  • Flow Cytometry
  • Fusion Proteins, bcr-abl / genetics
  • Humans
  • Immunoblotting
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics*
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Neoplasms, Experimental / drug therapy*
  • Neoplasms, Experimental / genetics
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrimidines / pharmacology*
  • Thiazoles / pharmacology*
  • Xenograft Model Antitumor Assays
  • src-Family Kinases / antagonists & inhibitors

Substances

  • Antineoplastic Agents
  • FB2 compound
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Thiazoles
  • Fusion Proteins, bcr-abl
  • src-Family Kinases