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Updated: Jun 23, 2026

Real-Time Monitoring of Aurora kinase A Activation using Conformational FRET Biosensors in Live Cells
06:29

Real-Time Monitoring of Aurora kinase A Activation using Conformational FRET Biosensors in Live Cells

Published on: July 30, 2020

A class of 2,4-bisanilinopyrimidine Aurora A inhibitors with unusually high selectivity against Aurora B

Ignacio Aliagas-Martin1, Dan Burdick, Laura Corson

  • 1Department of Small Molecule Drug Discovery, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.

Journal of Medicinal Chemistry
|May 1, 2009
PubMed

Insights

Researchers developed selective Aurora A kinase inhibitors, overcoming challenges posed by similar ATP-binding sites. A single amino acid difference explains selectivity, offering a new strategy for targeted cancer therapies.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Aurora kinases (A and B) are crucial for cell division and are targets for cancer drugs.
  • Existing pan-Aurora inhibitors show antitumor effects, but selective inhibitors are needed.
  • The structural similarity between Aurora A and B ATP-binding sites hinders selective inhibition.

Purpose of the Study:

  • To identify and characterize selective inhibitors for Aurora A kinase.
  • To elucidate the structural basis for Aurora A selectivity over Aurora B.
  • To explore the potential of exploiting amino acid differences for drug design.

Main Methods:

  • Enzymatic and cellular phenotypic assays were used to evaluate inhibitor selectivity.
  • Crystal structures of Aurora A in complex with novel inhibitors were determined.
  • Site-directed mutagenesis was employed to investigate the role of specific amino acid residues.

Main Results:

  • A novel class of bisanilinopyrimidine compounds demonstrated high selectivity for Aurora A over Aurora B.
  • Crystal structures revealed inhibitor binding to Aurora A.
  • A single amino acid difference (E161 in Aurora B vs. T217 in Aurora A) was identified as key to selectivity.
  • Mutating this residue swapped the inhibition profiles of Aurora A and B.

Conclusions:

  • The identified amino acid difference is critical for achieving selective Aurora A inhibition.
  • This finding provides a structural basis for designing highly selective Aurora A inhibitors.
  • Exploiting this residue difference offers a promising strategy for developing targeted cancer therapies with improved efficacy and reduced side effects.

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