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. ©2010 AACR.

Inhibiting Aurora Kinases Reduces Tumor Growth and Suppresses Tumor Recurrence after Chemotherapy in Patient-Derived Triple-Negative Breast Cancer Xenografts

“…This is consistent with other preclinical studies showing that Aurora kinases inhibitors alone do not induce tumor regression in solid cancers (10,21,(31)(32)(33). Treatment with the Aurora kinase inhibitors PF-03814735 and MK-0457 delayed the growth of colon and ovarian xenografts (31,32).…”

“…Consistent with other studies, pHisH3 reduction was rapid and reversible (31,32). Interestingly, pHisH3 reduction was also observed in a xenograft model that did not respond to AS703569, suggesting that inhibition of Aurora kinases activity alone may not be sufficient to arrest cell proliferation in resistant tumors and these might escape treatment through alternative pathways.…”

An Integrated Genomic Approach to Identify Predictive Biomarkers of Response to the Aurora Kinase Inhibitor PF-03814735

“…Indeed, analyses of MYC-and MYCN-driven models indicated common downstream consequences of Aurora B inhibition, including a decrease in phosphohistone H3 and increased cell ploidy. These findings are consistent with the molecular phenotype of PF-03814735 as well as other AURKB inhibitors (6,7,10,23).…”

Biological Characterization of TAK-901, an Investigational, Novel, Multitargeted Aurora B Kinase Inhibitor

“…In vivo combination with TAK-901 resulted in decreased tumor growth compared with chemotherapy alone, offering the potential for enhanced antitumor activity. The ability to combine with Aurora B kinase inhibitors may be broad as several other Aurora kinase inhibitors have also shown potentiation with different antimitotic agents in cancer cells and xenograft models (34,44,45). Because many cancers are sustained by abnormalities in multiple pathways, combination of TAK-901 with standard-of-care and/or other targeted agents with additive or synergistic mechanisms of action may increase treatment efficacy.…”

“…However, many pan-Aurora kinase inhibitors generate a similar polyploid cellular phenotype, which is a hallmark of Aurora B inactivation (11,14). More than 10 small-molecule inhibitors have entered early clinical development, including selective inhibitors of Aurora A (23)(24)(25), B, or C (26)(27)(28)(29) and panAurora kinase inhibitors (30)(31)(32)(33)(34)(35).…”