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PF-03814735, an orally bioavailable small molecule aurora kinase inhibitor for cancer therapy

Jitesh P Jani1, Joel Arcari, Vincent Bernardo

  • 1Pfizer Oncology, Pfizer Groton/New London Laboratories, 50 Pequot Avenue, New London, CT 06320, USA.

Molecular Cancer Therapeutics
|April 1, 2010
PubMed

Insights

PF-03814735, an inhibitor of Aurora kinases, effectively blocks cell division and reduces tumor growth in preclinical models. This drug shows promise for treating advanced solid tumors and warrants further clinical investigation.

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Pharmacology

Background:

  • Aurora kinases (Aurora1 and Aurora2) are crucial for mitosis, chromosome segregation, and cell division.
  • Aberrant Aurora kinase activity, particularly Aurora2 overexpression, is linked to various cancers, including breast, colon, and ovarian cancers.

Purpose of the Study:

  • To evaluate PF-03814735, a novel inhibitor targeting Aurora1 and Aurora2 kinases, for its anti-cancer potential.
  • To assess the in vitro and in vivo efficacy of PF-03814735 in preclinical cancer models.

Main Methods:

  • Utilized intact cells to assess the biochemical effects of PF-03814735 on Aurora kinase activity and downstream targets.
  • Administered PF-03814735 orally to mice with human xenograft tumors to evaluate its impact on tumor growth and phosphohistone H3 levels.
  • Investigated the combination therapy of PF-03814735 with docetaxel in xenograft models.

Main Results:

  • PF-03814735 effectively reduced phospho-Aurora1, phosphohistone H3, and phospho-Aurora2 levels in cells.
  • The drug induced a block in cytokinesis, leading to polyploidy and inhibited cell proliferation.
  • Oral PF-03814735 administration in mice significantly inhibited tumor growth and reduced phosphohistone H3 in tumors.
  • Combination therapy with docetaxel demonstrated additive tumor growth inhibition.

Conclusions:

  • PF-03814735 is a potent inhibitor of Aurora kinases with significant anti-tumor activity in preclinical models.
  • The drug's mechanism involves disrupting mitosis and cytokinesis, leading to cancer cell death.
  • Results support the clinical development of PF-03814735 for treating advanced solid tumors.

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