A pentacyclic aurora kinase inhibitor (AKI-001) with high in vivo potency and oral bioavailability

J Med Chem. 2008 Aug 14;51(15):4465-75. doi: 10.1021/jm800052b. Epub 2008 Jul 17.

Abstract

Aurora kinase inhibitors have attracted a great deal of interest as a new class of antimitotic agents. We report a novel class of Aurora inhibitors based on a pentacyclic scaffold. A prototype pentacyclic inhibitor 32 (AKI-001) derived from two early lead structures improves upon the best properties of each parent and compares favorably to a previously reported Aurora inhibitor, 39 (VX-680). The inhibitor exhibits low nanomolar potency against both Aurora A and Aurora B enzymes, excellent cellular potency (IC50 < 100 nM), and good oral bioavailability. Phenotypic cellular assays show that both Aurora A and Aurora B are inhibited at inhibitor concentrations sufficient to block proliferation. Importantly, the cellular activity translates to potent inhibition of tumor growth in vivo. An oral dose of 5 mg/kg QD is well tolerated and results in near stasis (92% TGI) in an HCT116 mouse xenograft model.

Publication types

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

MeSH terms

  • Administration, Oral
  • Animals
  • Aurora Kinase A
  • Aurora Kinase B
  • Aurora Kinases
  • Benzimidazoles / chemical synthesis
  • Benzimidazoles / chemistry
  • Biological Availability
  • Cell Line, Tumor
  • Crystallography, X-Ray
  • Dogs
  • Heterocyclic Compounds, 4 or More Rings / administration & dosage
  • Heterocyclic Compounds, 4 or More Rings / chemical synthesis
  • Heterocyclic Compounds, 4 or More Rings / chemistry*
  • Heterocyclic Compounds, 4 or More Rings / pharmacokinetics*
  • Humans
  • Lactams / chemistry
  • Mice
  • Models, Molecular
  • Molecular Structure
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacokinetics*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein Serine-Threonine Kinases / metabolism
  • Rats

Substances

  • 8-ethyl-2,5,6,12-tetrahydro-3,10,10-trimethyl-9-oxopyrazolo(4',3'-6,7)cyclohepta(1,2-b)pyrrolo(2,3-f)indole
  • Benzimidazoles
  • Heterocyclic Compounds, 4 or More Rings
  • Lactams
  • Protein Kinase Inhibitors
  • AURKB protein, human
  • Aurka protein, mouse
  • Aurka protein, rat
  • Aurkb protein, mouse
  • Aurkb protein, rat
  • Aurora Kinase A
  • Aurora Kinase B
  • Aurora Kinases
  • Protein Serine-Threonine Kinases