PF-03814735 is a novel, potent, orally bioavailable, reversible small-molecule Aurora kinase inhibitor with IC50 of 0.8, 5, 10 and 22 nM for Aurora 1, Aurora 2, Flt 1 and FAk, respectively. Aurora kinases are serine- threonine kinases that play essential roles in mitotic checkpoint control during mitosis. PF-03814735?possesses potential antineoplastic activity. Aurora kinase inhibitor PF-03814735 binds to and blocks Aurora kinases A and B, which may result in the prevention of cellular division and proliferation in tumor cells that overexpress these kinases. In intact cells, the preventive activity of PF-03814735 on the Aurora1 and Aurora2 kinases attenuates levels of phospho-Aurora1, phosphohistone H3, and phospho-Aurora2. PF-03814735 generates a block in cytokinesis, leading to prevention of cell proliferation and the formation of polyploid multinucleated cells. Although PF-03814735 generates significant prevention of several other protein kinases, the predominant biochemical effects in cellular assays are consistent with inhibition of Aurora kinases. Once-daily oral injection of PF-03814735 to mice bearing human xenograft tumors generates an attenuation 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. PF-03814735 is originally developed by Pfizer. The phase I clinical trials for the treatment of solid tumors has been completed.
|Cell lines||HCT-116 cell|
|Preparation method||Growing cell lines in appropriate media and evaluating 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, culturing HL-60 cell cultures in RPMI medium supplemented with 15% heat-inactivated fetal bovine serum and exposing them 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. Evaluating continuous exposure to PF-03814735 for 72 hours . Determining cell counts by a Coulter Counter.|
|Incubation time||4, 8, 12, 24, 48, or 72 hours|
|Animal models||HCT116 tumors are implanted s.c. on the right flank of nude mice.|
|Formulation||PF-03814735 is formulated as a solution in cremophor EL [cremophor/ethanol/0.9% saline (12.5%/12.5%/75%)].|
|Dosages||10, 20, 30 mg/kg|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Related Aurora Kinase Products|
SNS-314 is a potent and selective inhibitor of Aurora A, Aurora B and Aurora C with IC50 of 9 nM, 31 nM, and 3 nM, respectively.
GSK1070916 is a reversible and ATP-competitive inhibitor of Aurora B/C with IC50 of 3.5 nM/6.5 nM. It displays >100-fold selectivity against the closely related Aurora A-TPX2 complex.
PHA-680632 is potent inhibitor of Aurora A, Aurora B and Aurora C with IC50 of 27 nM, 135 nM and 120 nM, respectively. It has 10- to 200-fold higher IC50 for FGFR1, FLT3, LCK, PLK1, STLK2, and VEGFR2/3.
MK-5108 (VX-689) is a highly selective Aurora A inhibitor with IC50 of 0.064 nM and is 220- and 190-fold more selective for Aurora A than Aurora B/C, while it inhibits TrkA with less than 100-fold selectivity.
MK-8745 is a potent and selective Aurora A inhibitor with IC50 of 0.6 nM, more than 450-fold selectivity for Aurora A over Aurora B.
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