Synthesis and biological evaluation of a series of novel inhibitor of Nek2/Hec1 analogues

J Med Chem. 2009 Mar 26;52(6):1757-67. doi: 10.1021/jm8015969.

Abstract

High expression in cancer 1 (Hec1) is an oncogene overly expressed in many human cancers. Small molecule inhibitor of Nek2/Hec1 (INH) targeting the Hec1 and its regulator, Nek2, in the mitotic pathway, was identified to inactivate Hec1/Nek2 function mediated by protein degradation that subsequently leads to chromosome mis-segregation and cell death. To further improve the efficacy of INH, a series of INH analogues were designed, synthesized, and evaluated. Among these 33 newly synthesized analogues, three of them, 6, 13, and 21, have 6-8 fold more potent cell killing activity than the previous lead compound INH1. Compounds 6 and 21 were chosen for analyzing the underlying action mechanism. They target directly the Hec1/Nek2 pathway and cause chromosome mis-alignment as well as cell death, a mechanism similar to that of INH1. This initial exploration of structural/functional relationship of INH may advance the progress for developing clinically applicable INH analogue.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Cell Line, Tumor
  • Flow Cytometry
  • Humans
  • Magnetic Resonance Spectroscopy
  • NIMA-Related Kinases
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / pharmacology*
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Spectrometry, Mass, Electrospray Ionization

Substances

  • Protein Kinase Inhibitors
  • NEK2 protein, human
  • NIMA-Related Kinases
  • Protein-Serine-Threonine Kinases