Molecular Weight(MW): 474.48
PF-03814735 is a novel, potent and reversible inhibitor of Aurora A/B with IC50of 0.8 nM/5 nM, is less potent to Flt3, FAK, TrkA, and minimally active to Met and FGFR1. Phase 1.
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|Description||PF-03814735 is a novel, potent and reversible inhibitor of Aurora A/B with IC50of 0.8 nM/5 nM, is less potent to Flt3, FAK, TrkA, and minimally active to Met and FGFR1. Phase 1.|
In intact cells, the inhibitory activity of PF-03814735 on the Aurora1 and Aurora2 kinases reduces levels of phospho-Aurora1 (Thr 232, a sensitive marker of Aurora1 activity, with IC50 ~ 20 nM), phosphohistone H3 (with IC50 ~ 50 nM), and phospho-Aurora2 (with IC50 ~150 nM). PF-03814735 produces a block in cytokinesis, resulting in inhibition of cell proliferation and the formation of polyploid multinucleated cells.  A recent research indicates small cell lung cancer (SCLC) and, to a lesser extent, colon cancer lines are very sensitive to PF-03814735. The status of the Myc gene family and retinoblastoma pathway members significantly correlates with the efficacy of PF-03814735. 
|In vivo||Once-daily oral dosing of ≥20 mg/kg of PF-03814735 for 10 days to mice bearing HCT-116 xenografts resulted in statistically significant and dose-dependent tumor growth inhibition of ≥50% relative to vehicle-treated mice. The inhibition is associated with a reduction in phosphorylated histone H3 levels. Significant single-agent antitumor efficacy is observed in five additional xenograft tumor models, including A2780 ovarian carcinoma, MDA-MB-231 breast carcinoma, colo-205 and SW620 colorectal carcinomas, and HL-60 acute promyelocytic leukemia.  In vivo experiments with two SCLC xenograft models confirms the sensitivity of Myc gene-driven models to PF-03814735 and a possible schedule dependence of MYC/c-Myc-driven tumors. |
Recombinant Kinase Assays:Aurora1 and Aurora2 proteins are produced as full-length His-tag recombinant proteins expressed in insect cells. For the Aurora2 kinase assay, phosphorylation of the substrate peptide by recombinant Aurora2 protein is assessed by a Z'-LYTE assay at 3 to 300 μM ATP and various concentrations of PF-03814735 over 60 minutes, at a substrate peptide concentration of 2 μM (biotinylated LRRWSLG, ×4). Phosphorylation is linear over this time for all conditions. For the Aurora1 kinase assay, phosphorylation of the substrate peptide by recombinant Aurora1 protein is assessed by a scintillation proximity assay in a 96-well plate format in which the incorporation of 33P into the peptide substrate (biotinylated LRRWSLG, ×4) is measured by capturing the peptide on a streptavidin scintillation proximity assay bead.
|In vitro||DMSO||0.4 mg/mL (0.84 mM)|
|In vivo||Add solvents individually and in order:
2% Cremophor EL, 2% N,N-dimethylacetamide, pH 5.0
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Clinical Trial Information
|NCT Number||Recruitment||Conditions||Sponsor/Collaborators||Start Date||Phases|
|NCT00424632||Completed||Solid Tumors||Pfizer||November 2006||Phase 1|
Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.
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