Design and synthesis of Coenzyme A analogues as Aurora kinase A inhibitors: An exploration of the roles of the pyrophosphate and pantetheine moieties

Bioorg Med Chem. 2020 Nov 15;28(22):115740. doi: 10.1016/j.bmc.2020.115740. Epub 2020 Sep 5.

Abstract

Coenzyme A (CoA) is a highly selective inhibitor of the mitotic regulatory enzyme Aurora A kinase, with a novel mode of action. Herein we report the design and synthesis of analogues of CoA as inhibitors of Aurora A kinase. We have designed and synthesised modified CoA structures as potential inhibitors, combining dicarbonyl mimics of the pyrophosphate group with a conserved adenosine headgroup and different length pantetheine-based tail groups. An analogue with a -SH group at the end of the pantotheinate tail showed the best IC50, probably due to the formation of a covalent bond with Aurora A kinase Cys290.

Keywords: Aurora A kinase; CoA; Inhibitor; Pantetheine; Pyrophosphate isostere.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aurora Kinase A / antagonists & inhibitors*
  • Aurora Kinase A / metabolism
  • Coenzyme A / chemical synthesis
  • Coenzyme A / chemistry
  • Coenzyme A / pharmacology*
  • Diphosphates / chemistry
  • Diphosphates / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Pantetheine / chemistry
  • Pantetheine / pharmacology*
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Structure-Activity Relationship

Substances

  • Diphosphates
  • Protein Kinase Inhibitors
  • Pantetheine
  • diphosphoric acid
  • Aurora Kinase A
  • Coenzyme A