PF-03814735 is a reversible inhibitor of both Aurora A and B kinases, with IC50 values of 0.8 nM and 5 nM respectively in enzymatic assays, making the aurora kinase inhibitor PF-03814735 one of the most extensively profiled dual-Aurora tools available to cancer researchers. The compound carries antineoplastic potential through inhibition of cellular division and proliferation in tumor cells overexpressing Aurora kinases A and B. The PF-03814735 molecular weight is 474.49 g/mol (formula C23H25F3N6O2). The PF-03814735 molecular structure is an azatricyclic core bridged to a trifluoromethylpyrimidine bearing a cyclobutylamino substituent; this PF-03814735 chemical structure (CAS 942487-16-3) is reversible and ATP-competitive at the kinase active site.
Application of PF-03814735
Aurora kinases A and B regulate distinct phases of mitosis: Aurora A governs centrosome maturation and spindle assembly, while Aurora B controls chromosome alignment and cytokinesis at the midbody. Because both kinases are frequently overexpressed in proliferating tumors, dual inhibition with the PF-03814735 structure offers researchers a way to disrupt mitotic progression at two independent checkpoints simultaneously, rather than relying on partial pathway blockade from a single-target compound. The compound has also been investigated outside oncology, where it enhances adeno-associated virus transduction of retina cells in vitro and in vivo.
In Vitro
PF-03814735 inhibits phosphorylation of Aurora B, histone H3, and Aurora A in cultured MDA-MB-231 cells with IC50 values of approximately 20, 50, and 150 nM respectively, and blocks cytokinesis while inhibiting cellular proliferation in HCT-116, HL-60, A549, and H125 tumor cell lines. Inhibitory effects on phosphorylated histone H3 and phosphorylated Aurora A occur rapidly, with marked depletion within 30 minutes of treatment, consistent with the compound's reversible binding mode. The compound shows particular sensitivity toward small cell lung cancer cell lines and tumors driven by Myc family genes.
In Vivo
PF-03814735 shows in vivo efficacy in an HCT-116 tumor xenograft mouse model, and once-daily oral administration produces a reduction in phosphohistone H3 in tumors at tolerable doses, resulting in significant inhibition of tumor growth. Combining PF-03814735 with docetaxel in xenograft models showed additive tumor growth inhibition, a finding relevant to researchers designing combination regimens around mitotic checkpoint inhibitors.
Biochemical and Physiological Actions
PF-03814735 acts by competitively binding to the ATP-binding site of Aurora A and Aurora B, thereby disrupting their kinase activity. Loss of Aurora B function specifically blocks cytokinesis, the final separation of daughter cells, which leads cells to re-enter the cell cycle without completing division. This produces polyploid and multinucleated cells as a direct consequence of the cytokinesis block. Beyond the Aurora kinases, profiling against a panel of 220 kinases identified 19 additional targets with over 90% inhibition at 100 nmol/L, including Flt1, FAK, TrkA, Met, and FGFR1.
Features and Benefits of PF-03814735
The value of PF-03814735 as a research compound lies in its combination of sub-nanomolar Aurora kinase potency, oral bioavailability, and a documented mechanistic signature – polyploidy and multinucleation – that gives researchers a clear phenotypic readout for confirming on-target activity. Its characterized secondary kinase profile and demonstrated combinability with chemotherapeutics such as docetaxel make it a well-validated tool for studies of mitotic checkpoint biology and combination treatment strategies in oncology research.
Powered by Bioz