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PF-03814735

Cat. No. M3221
PF-03814735 Structure
Size Price Availability
5mg USD 120  USD120 Out of stock
10mg USD 220  USD220 Out of stock
50mg USD 700  USD700 Out of stock
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Quality Control
  • Current batch:
  • Purity >98%
  • COA
  • MSDS
Biological Activity

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.

Protocol
Cell Experiment
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.
Concentrations 300 nM
Incubation time 4, 8, 12, 24, 48, or 72 hours
Animal Experiment
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
Administration Administered orally
Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)
Species Mouse Rat Rabbit Guinea pig Hamster Dog
Weight (kg) 0.02 0.15 1.8 0.4 0.08 10
Body Surface Area (m2) 0.007 0.025 0.15 0.05 0.02 0.5
Km factor 3 6 12 8 5 20
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 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 Compound A of 10 mg/kg.

Chemical Information
Molecular Weight 474.48
Formula C23H25F3N6O2
CAS Number 942487-16-3
Purity >98%
Solubility DMSO
Storage at -20°C
References

[1] Sevim Dalva-Aydemir, et al. Toward In Vitro Epigenetic Drug Design for Thyroid Cancer: The Promise of PF-03814735, an Aurora Kinase Inhibitor

[2] Sailu Sarvagalla, et al. Structural Biology Insight for the Design of Sub-type Selective Aurora Kinase Inhibitors

[3] Kenneth E Hook, et al. An integrated genomic approach to identify predictive biomarkers of response to the aurora kinase inhibitor PF-03814735

[4] Patrick Schffski, et al. Phase I, open-label, multicentre, dose-escalation, pharmacokinetic and pharmacodynamic trial of the oral aurora kinase inhibitor PF-03814735 in advanced solid tumours

[5] Jitesh P Jani, et al. PF-03814735, an orally bioavailable small molecule aurora kinase inhibitor for cancer therapy

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Keywords: PF-03814735 supplier, Aurora Kinase, inhibitors

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