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

Abstract

The Aurora family of highly related serine/threonine kinases plays a key role in the regulation of mitosis. Aurora1 and Aurora2 play important but distinct roles in the G(2) and M phases of the cell cycle and are essential for proper chromosome segregation and cell division. Overexpression and amplification of Aurora2 have been reported in different tumor types, including breast, colon, pancreatic, ovarian, and gastric cancer. PF-03814735 is a novel, potent, orally bioavailable, reversible inhibitor of both Aurora1 and Aurora2 kinases that is currently in phase I clinical trials for the treatment of advanced solid tumors. In intact cells, the inhibitory activity of PF-03814735 on the Aurora1 and Aurora2 kinases reduces levels of phospho-Aurora1, phosphohistone H3, and phospho-Aurora2. PF-03814735 produces a block in cytokinesis, resulting in inhibition of cell proliferation and the formation of polyploid multinucleated cells. Although PF-03814735 produces significant inhibition of several other protein kinases, the predominant biochemical effects in cellular assays are consistent with inhibition of Aurora kinases. Once-daily oral administration of PF-03814735 to mice bearing human xenograft tumors produces a reduction in phosphohistone H3 in tumors at doses that are tolerable and that result in significant inhibition of tumor growth. The combination of PF-03814735 and docetaxel in xenograft mouse tumor models shows additive tumor growth inhibition. These results support the clinical evaluation of PF-03814735 in cancer patients. Mol Cancer Ther; 9(4); 883-94. (c)2010 AACR.

• Authors: Jitesh P Jani, Joel Arcari, Vincent Bernardo, Samit K Bhattacharya, David Briere, Bruce D Cohen, Kevin Coleman, James G Christensen, Erling O Emerson, Amy Jakowski, Kenneth Hook, Gerrit Los, James D Moyer, Ingrid Pruimboom-Brees, Leslie Pustilnik, Ann Marie Rossi, Stefan J Steyn, Chunyan Su, Konstantinos Tsaparikos, Donn Wishka, Kwansik Yoon, John L Jakubczak
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 9 Issue 4 Pg. 883-94 (Apr 2010) ISSN: 1538-8514 [Electronic] United States
• PMID: 20354118 (Publication Type: Journal Article)

Chemical References

• Heterocyclic Compounds, 3-Ring
• Histones
• N-(2-(6-(4-cyclobutylamino-5-trifluoromethylpyrimidine-2-ylamino)-1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-9-yl)-2-oxo-ethyl)acetamide
• Protein Kinase Inhibitors
• Pyrimidines
• Aurora Kinases
• Protein Serine-Threonine Kinases

Topics

• Administration, Oral
• Animals
• Aurora Kinases
• Biological Availability
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Female
• Heterocyclic Compounds, 3-Ring (administration & dosage, pharmacokinetics, pharmacology, therapeutic use)
• Histones (metabolism)
• Humans
• Mice
• Mice, Nude
• Neoplasms (drug therapy, enzymology, pathology)
• Phosphorylation (drug effects)
• Protein Kinase Inhibitors (chemistry, pharmacokinetics, pharmacology, therapeutic use)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Pyrimidines (administration & dosage, pharmacokinetics, pharmacology, therapeutic use)
• Substrate Specificity (drug effects)
• Xenograft Model Antitumor Assays