Background
PF-03814735 is a potent, orally bioavailable, reversible inhibitor of both Aurora1 and Aurora2 kinases with IC50 values of 0.8nM and 5nM, respectively [1].
PF-03814735 is an ATP competitive inhibitor of Aurora kinases. It also shows inhibition of other protein kinases at 100nM, such as Flt1, FAK, TrkA, Met, and FGFR1. The immunofluorescence imaging analysis shows PF-03814735 can inhibit the phosphorylation of Aurora1, Aurora 2 as well as histone H3 in MDA-MB-231 cells. This inhibition is rapid and reversible. The inhibition of phosphorylated histone H3 also occurs in athymic mice bearing HCT-116 xenografts. PF-03814735 induces the formation of polyploid cells and multinucleated cells due to the block in cytokinesis secondary. Moreover, PF-03814735 treatment results in a reduction of cell proliferation in vitro (such as HL-60, A549, and H125) and a inhibition of tumor growth in vivo (human xenograft mouse models, such as A2780 ovarian carcinoma and HCT-116) [1].
参考文献:
[1] 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-03814735, an orally bioavailable small molecule aurora kinase inhibitor for cancer therapy. Mol Cancer Ther. 2010 Apr;9(4):883-94.
PF-03814735 是一种有效的、具有口服生物利用度的 Aurora1 和 Aurora2 激酶的可逆抑制剂，IC50 值分别为 0.8nM 和 5nM [1]。
PF-03814735 是一种 ATP 竞争性抑制剂极光激酶。它还显示在 100nM 时抑制其他蛋白激酶，例如 Flt1、FAK、TrkA、Met 和 FGFR1。免疫荧光成像分析表明，PF-03814735 可以抑制 MDA-MB-231 细胞中 Aurora1、Aurora 2 以及组蛋白 H3 的磷酸化。这种抑制是快速和可逆的。磷酸化组蛋白 H3 的抑制也发生在携带 HCT-116 异种移植物的无胸腺小鼠中。由于继发性胞质分裂受阻，PF-03814735 诱导多倍体细胞和多核细胞的形成。此外，PF-03814735 治疗导致体外细胞增殖减少（如 HL-60、A549 和 H125）和抑制体内肿瘤生长（人异种移植小鼠模型，如 A2780 卵巢癌和 HCT-116 ) [1].
Protocol
| Cell experiment [1]: |
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Cell lines
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MDA-MB-231 cells, various tumor types (HCT-116, HL-60, A549, and H125) as well as tumor cell lines of rat (C6), mouse (L1210), and dog (MDCK) origin.
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Preparation method
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The solubility of this compound in DMSO is > 10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.
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Reacting condition
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1-1000 nM; 4, 8, 12, 24, and 48 h
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Applications
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In MDA-MB-231 cells, PF-03814735 markedly reduced levels of Aurora1 phosphorylated on Thr 232 and the phosphorylation of histone H3 on Ser10 with IC50 values of 20 nmol/L and 50 nmol/L. In various tumor cell lines, PF-03814735 resulted in a reduction in cell number with IC50 values ranging from 42 to 150 nmol/L. PF-03814735 at 300 nmol/L produced near-complete inhibition of cell proliferation.
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| Animal experiment [1]: |
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Animal models
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Athymic mice bearing s.c. HCT-116 human colorectal cancer xenografts
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Dosage form
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10, 20, and 30 mg/kg; oral gavage for 10 days
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Application
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In athymic mice bearing s.c. HCT-116 human colorectal cancer xenografts, PF-03814735 (≥20 mg/kg) resulted in statistically significant and dose-dependent tumor growth inhibition of ≥50% relative to vehicle-treated mice. The tumor growth inhibition was associated with a reduction in phosphorylated histone H3 levels of ≥50% for approximately 5 hours each day for 10 days.
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Other notes
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Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.
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参考文献:
[1] 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-03814735, an orally bioavailable small molecule aurora kinase inhibitor for cancer therapy. Mol Cancer Ther. 2010 Apr;9(4):883-94.
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