HS-438, a new inhibitor of imatinib-resistant BCR-ABL T315I mutation in chronic myeloid leukemia

Cancer Lett. 2014 Jun 28;348(1-2):50-60. doi: 10.1016/j.canlet.2014.03.012. Epub 2014 Mar 18.

Abstract

Imatinib is a selective breakpoint cluster region-Abelson (BCR-ABL) tyrosine kinase inhibitor (TKI) that has significantly improved the prognosis of patients with chronic myeloid leukemia (CML). However, T315I gene mutations of the BCR-ABL kinase domain have been shown to confer resistance to imatinib. In the present study, we synthesized a novel BCR-ABL inhibitor, HS-438, and identified its anti-leukemic effects in vitro and in vivo. We found that HS-438 strongly inhibited the expression of BCR-ABL signaling pathways in wild-type BCR-ABL (BaF3/WT) cells as well as T315I-mutated BCR-ABL (BaF3/T315I) cells with resistance to imatinib. HS-438 induced cell cycle arrest, particularly during the G0/G1 cell cycle phase, and induced apoptosis. In BaF3/T315I xenograft models, HS-438 significantly delayed tumor growth, unlike imatinib. In summary, we suggest that HS-438 may be a novel drug candidate with the therapeutic potential to target BCR-ABL and overcome imatinib resistance in patients with CML.

Keywords: BCR-ABL; Chronic myeloid leukemia; HS-438; T315I.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Benzamides / pharmacology*
  • Benzothiazoles / metabolism
  • Benzothiazoles / pharmacology*
  • Binding Sites
  • Cell Cycle Checkpoints / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Drug Resistance, Neoplasm* / genetics
  • Fusion Proteins, bcr-abl / antagonists & inhibitors*
  • Fusion Proteins, bcr-abl / genetics*
  • Fusion Proteins, bcr-abl / metabolism
  • Imatinib Mesylate
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / enzymology
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
  • Male
  • Membrane Potential, Mitochondrial / drug effects
  • Mice
  • Mice, Nude
  • Models, Molecular
  • Mutation*
  • Piperazines / pharmacology*
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrimidines / pharmacology*
  • Time Factors
  • Tumor Burden / drug effects
  • Urea / analogs & derivatives*
  • Urea / metabolism
  • Urea / pharmacology

Substances

  • 1-(2-hydroxyethyl)-3-(6-(2-methoxyphenyl)benzo(d)thiazol-2-yl)urea
  • Antineoplastic Agents
  • Benzamides
  • Benzothiazoles
  • Piperazines
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Imatinib Mesylate
  • Urea
  • Fusion Proteins, bcr-abl