PF-04880594 是一种有效的选择性 RAF 抑制剂。 PF-04880594 抑制野生型和突变型 BRAF 和 CRAF。 PF-04880594 显示出抗肿瘤活性。
PF-04880594 is a selective inhibitor of B-Raf, B-RafV599E and c-Raf with IC50 value of 0.19 nM, 0.13 nM and 0.39 nM, respectively [1].
Raf is a serine/threonine protein kinase and plays an important role in the MAPK/ERK signaling pathway. It has been revealed that Raf involves in cancers and developmental syndromes and its inhibitors are regarded as a promising target for cancer treatment [2, 3].
PF-04880594 is a potent Raf inhibitor. When tested with GTL16 and GTL16 resistant cell clones, PF-04880594 treatment significantly decreased cell viability and ERK activity [2]. In 3D culture model of RHE cells (histologic similar to human epidermal lasers), PF-04880594 treatment (62.5 nmol/L, 2 d) significantly induced necrosis with ghost cells accounting for nearly 50% to 60% of the culture thickness via inducing p-ERK expression level [3].
Treated nude mice model with PF-04880594 (10-40 mg/kg, twice daily for 3 weeks) and then mice were sacrificed for further study. The results revealed that PF-04880594 treatment induced ERK phosphorylation and B-Raf-c-Raf dimerization in multiple epithelial tissues which phenomenon could be attenuated by PD-0325901 [3].
参考文献:
[1].? Palmer C, Cui J, Deal J, Gu D, Guo C, Kephart S, et al. Discovery of potent, selective inhibitors of mutant B-Raf. (Abstract # MEDI-251). Abstracts of Papers, 242nd ACS National Meeting & Exposition 2011.
[2].? Lee, N. V. Lira, M. E. Pavlicek, A., et al. A novel SND1-BRAF fusion confers resistance to c-Met inhibitor PF-04217903 in GTL16 cells through [corrected] MAPK activation [J]. PLoS One, 2012, 7(6): e39653.
[3].? Vince R. Torti, Donald Wojciechowicz, Wenyue Hu, et al. Epithelial Tissue Hyperplasia Induced by the RAF Inhibitor PF-04880594 Is Attenuated by a Clinically Well-Tolerated Dose of the MEK Inhibitor PD-0325901 [J]. Mol Cancer Ther, 2012, 11(10):2274-2283.
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