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.
Pál Gyulavári  1 ,  Bálint Szokol  2 ,  István Szabadkai  2 ,  Diána Brauswetter  1 ,  Péter Bánhegyi  2 ,  Attila Varga  1 ,  Péter Markó  2 ,  Sándor Boros  2 ,  Eszter Illyés  2 ,  Csaba Szántai-Kis  2 ,  Marcell Krekó  3 ,  Zsófia Czudor  3 ,  László Őrfi  4
Affiliations
  • 1. MTA-SE Pathobiochemistry Research Group, 37-43. Tűzoltó u., Budapest 1094, Hungary.
  • 2. Vichem Chemie Research Ltd., 15. Herman Ottó u., Budapest 1022, Hungary.
  • 3. Department of Pharmaceutical Chemistry, Semmelweis University, 9. Hőgyes Endre u., Budapest 1092, Hungary.
  • 4. Vichem Chemie Research Ltd., 15. Herman Ottó u., Budapest 1022, Hungary; Department of Pharmaceutical Chemistry, Semmelweis University, 9. Hőgyes Endre u., Budapest 1092, Hungary. Electronic address: [email protected].
PMID: 30143423 DOI: 10.1016/j.bmcl.2018.05.064
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.