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Aurora kinases and their inhibitors: more than one target and one drug

Patrizia Carpinelli1, Jürgen Moll

  • 1Nerviano Medical Sciences Srl. Viale Pasteur 10, 20014 Nerviano (Mi), Italy.

Advances in Experimental Medicine and Biology
|July 3, 2008
PubMed

Insights

Small molecule inhibitors targeting Aurora kinases impact mitosis differently, requiring tailored clinical development. PHA-739358, a selective inhibitor, shows promise for chronic myelogenous leukemia (CML) patients resistant to existing treatments.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Aurora kinase family members play critical roles in mitosis.
  • Differential inhibition of Aurora kinases leads to varied cellular responses.
  • Understanding these responses is crucial for developing effective small molecule inhibitors.

Purpose of the Study:

  • To compare the properties of advanced small molecule Aurora kinase inhibitors.
  • To present a case report on the development of PHA-739358.
  • To explore the potential of PHA-739358 in treating resistant chronic myelogenous leukemia (CML).

Main Methods:

  • Comparative analysis of advanced small molecule Aurora kinase inhibitors.
  • Case report detailing the development of PHA-739358.
  • Evaluation of PHA-739358's inhibitory profile against cancer-relevant targets, including Abl kinase mutants.

Main Results:

  • PHA-739358 is a spectrum-selective kinase inhibitor with dominant Aurora kinase inhibition.
  • PHA-739358 effectively inhibits both wild-type Abl and the multidrug-resistant Abl T315I mutant.
  • Clinical trials are ongoing to assess PHA-739358's efficacy in CML patients with treatment resistance.

Conclusions:

  • The clinical development of Aurora kinase inhibitors necessitates careful consideration of dose, schedule, and endpoints based on cellular responses.
  • PHA-739358's multi-target inhibition profile, including resistant Abl mutants, presents a novel therapeutic avenue for CML.
  • Further clinical evaluation is warranted to establish PHA-739358's role in managing resistant CML.

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