Inhibition of activated STAT5 in Bcr/Abl expressing leukemia cells with new pimozide derivatives

Bioorg Med Chem Lett. 2014 Sep 15;24(18):4568-4574. doi: 10.1016/j.bmcl.2014.07.069. Epub 2014 Aug 1.

Abstract

STATs are transcription factors acting as intracellular signaling after stimulation with cytokines, growth factors and hormones. STAT5 is also constitutively active in many forms of cancers, including chronic myelogenous leukemia, acute lymphoblastic leukemia and Hodgkin's lymphoma. Recently, literature reported that the neuroleptic drug pimozide inhibits STAT5 phosphorylation inducing apoptosis in CML cells. We undertook an investigation from pimozide structure, obtaining simple derivatives with cytotoxic and STAT5-inhibitory activity, two of them markedly more potent than pimozide.

Keywords: Apoptosis; BCR/ABL expressing leukemia; Cell growth inhibition; Pimozide; STAT5 inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Cell Cycle / drug effects
  • Cell Line
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Fusion Proteins, bcr-abl / metabolism*
  • Humans
  • K562 Cells
  • Molecular Structure
  • Phosphorylation / drug effects
  • Pimozide / chemical synthesis
  • Pimozide / chemistry
  • Pimozide / pharmacology*
  • STAT5 Transcription Factor / antagonists & inhibitors*
  • STAT5 Transcription Factor / genetics
  • STAT5 Transcription Factor / metabolism
  • Structure-Activity Relationship

Substances

  • STAT5 Transcription Factor
  • Pimozide
  • Fusion Proteins, bcr-abl