Kinesin spindle protein (KSP) inhibitors. Part 1: The discovery of 3,5-diaryl-4,5-dihydropyrazoles as potent and selective inhibitors of the mitotic kinesin KSP

Bioorg Med Chem Lett. 2005 Apr 15;15(8):2041-5. doi: 10.1016/j.bmcl.2005.02.055.

Abstract

Optimization of high-throughput screening (HTS) hits resulted in the discovery of 3,5-diaryl-4,5-dihydropyrazoles as potent and selective inhibitors of KSP. Dihydropyrazole 15 is a potent, cell-active KSP inhibitor that induces apoptosis and generates aberrant mitotic spindles in human ovarian carcinoma cells at low nanomolar concentrations. X-ray crystallographic evidence is presented which demonstrates that these inhibitors bind in an allosteric pocket of KSP distant from the nucleotide and microtubule binding sites.

MeSH terms

  • Cell Cycle Proteins / antagonists & inhibitors*
  • Cell Cycle Proteins / physiology
  • Cell Line, Tumor
  • Humans
  • Kinesin / antagonists & inhibitors*
  • Kinesin / physiology
  • Mitosis / drug effects*
  • Mitosis / physiology
  • Pyrazoles / chemistry*
  • Pyrazoles / pharmacology*
  • Spindle Apparatus / chemistry
  • Spindle Apparatus / drug effects*
  • Spindle Apparatus / physiology

Substances

  • Cell Cycle Proteins
  • Pyrazoles
  • Kinesin