Discovery and optimization of novel benzothiophene-3-carboxamides as highly potent inhibitors of Aurora kinases A and B

Bioorg Med Chem Lett. 2018 Oct 15;28(19):3265-3270. doi: 10.1016/j.bmcl.2018.05.064. Epub 2018 Jun 1.

Abstract

Aurora kinases as regulators of cell division have become promising therapeutic targets recently. Here we report novel, low molecular weight benzothiophene-3-carboxamide derivatives designed and optimized for inhibiting Aurora kinases. The most effective compound 36 inhibits Aurora kinases in vitro in the nanomolar range and diminishes HCT 116 cell viability blocking cytokinesis and inducing apoptosis. According to western blot analysis, the lead molecule inhibits Aurora kinases equipotently to VX-680 (Tozasertib) and similarly synergizes with other targeted drugs.

Keywords: Aurora kinase; Benzothiophene-3-carboxamide; Cancer; Kinase inhibitor; Targeted therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / chemistry*
  • Aurora Kinase A / antagonists & inhibitors*
  • Aurora Kinase B / antagonists & inhibitors*
  • HCT116 Cells
  • Humans
  • Inhibitory Concentration 50
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Thiophenes / chemistry*

Substances

  • Amides
  • Protein Kinase Inhibitors
  • Thiophenes
  • benzothiophene
  • AURKA protein, human
  • AURKB protein, human
  • Aurora Kinase A
  • Aurora Kinase B