"目录号: HY-14574
Cell Cycle/DNA DamageEpigenetics-
PF-03814735是口服生物相容性的可逆的Aurora抑制剂，对Aurora A，Aurora B，Flt 1和FAk的IC50分别为0.8，5，10和22 nM。
Aurora Kinase
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生物活性
Description
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 A, Aurora B, Flt 1 and FAk, respectively. IC50 Value: 0.8 nM(Aurora A); 5 nM(Aurora B); 10 nM(Flt1); 22 nM(FAK); 30 nM(TrkA)Target: Aurora A/BPF-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.
Clinical Trial
NCT00424632
Pfizer
Solid Tumors
November 2006
Phase 1
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References
[1].Sch?ffski P, Jones SF, Dumez H, Infante JR, Van Mieghem E, Fowst C, Gerletti P, Xu H, Jakubczak JL, English PA, Pierce KJ, Burris HA. Phase I, open-label, multicentre, dose-escalation, pharmacokinetic and pharmacodynamic trial of the oral aurora kinase i
[2].Tomillero A, Moral MA. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2008 Sep;30(7):543-88.
[3].Hook KE, Garza SJ, Lira ME, Ching KA, Lee NV, Cao J, Yuan J, Ye J, Ozeck M, Shi ST, Zheng X, Rejto PA, Kan JL, Christensen JG, Pavlicek A. An integrated genomic approach to identify predictive biomarkers of response to the aurora kinase inhibitor PF-0381
[4].Jani JP, Arcari J, Bernardo V, Bhattacharya SK, Briere D, Cohen BD, Coleman K, Christensen JG, Emerson EO, Jakowski A, Hook K, Los G, Moyer JD, Pruimboom-Brees I, Pustilnik L, Rossi AM, Steyn SJ, Su C, Tsaparikos K, Wishka D, Yoon K, Jakubczak JL. PF-038