SAR156497, an exquisitely selective inhibitor of aurora kinases

J Med Chem. 2015 Jan 8;58(1):362-75. doi: 10.1021/jm501326k. Epub 2014 Nov 24.

Abstract

The Aurora family of serine/threonine kinases is essential for mitosis. Their crucial role in cell cycle regulation and aberrant expression in a broad range of malignancies have been demonstrated and have prompted intensive search for small molecule Aurora inhibitors. Indeed, over 10 of them have reached the clinic as potential anticancer therapies. We report herein the discovery and optimization of a novel series of tricyclic molecules that has led to SAR156497, an exquisitely selective Aurora A, B, and C inhibitor with in vitro and in vivo efficacy. We also provide insights into its mode of binding to its target proteins, which could explain its selectivity.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology*
  • Aurora Kinase A / antagonists & inhibitors
  • Aurora Kinase A / chemistry
  • Aurora Kinase A / metabolism
  • Aurora Kinase B / antagonists & inhibitors
  • Aurora Kinase B / chemistry
  • Aurora Kinase B / metabolism
  • Aurora Kinase C / antagonists & inhibitors
  • Aurora Kinase C / chemistry
  • Aurora Kinase C / metabolism
  • Aurora Kinases / antagonists & inhibitors*
  • Aurora Kinases / chemistry
  • Aurora Kinases / metabolism
  • Benzimidazoles / chemistry
  • Benzimidazoles / metabolism
  • Benzimidazoles / pharmacology*
  • Female
  • HCT116 Cells
  • Humans
  • Mice, SCID
  • Models, Chemical
  • Models, Molecular
  • Molecular Structure
  • Neoplasms / drug therapy
  • Neoplasms / pathology
  • Protein Binding
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Structure, Tertiary
  • Quinolones / chemistry
  • Quinolones / metabolism
  • Quinolones / pharmacology*
  • Sf9 Cells
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / metabolism
  • Small Molecule Libraries / pharmacology*
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Benzimidazoles
  • Protein Kinase Inhibitors
  • Quinolones
  • Small Molecule Libraries
  • ethyl 8-oxo-9-(3-(1H-benzimidazol-2-yloxy)phenyl)-4,5,6,7,8,9-hexahydro-2H-pyrrolo(3,4-b)quinoline-3-carboxylate
  • Aurora Kinase A
  • Aurora Kinase B
  • Aurora Kinase C
  • Aurora Kinases