PF-03814735 942487-16-3

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Molecular Weight:

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.


Biological Activity


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.


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.

Method

Cell lines are grown in appropriate media and evaluated after 48 h of
exposure to either PF-03814735 or vehicle, followed by cell number
determination in a Coulter Counter. Proliferation (as measured by an
increase in cell number) is expressed as a percent of untreated
controls. To evaluate the PF-03814735 exposure time required for
antiproliferative activity, HL-60 cell cultures are cultured in RPMI
medium supplemented with 15% heat-inactivated fetal bovine serum and
exposed to various PF-03814735 concentrations for 4, 8, 12, 24, and 48
hours, followed by a washout step and incubation with growth media
without PF-03814735 for the remainder of the 72-h assay period.
Continuous exposure to PF-03814735 for 72 hours is also evaluated. Cell
counts are determined by a Coulter Counter.

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Product Categories : Epigenetics > Aurora Kinase Inhibitor