RAF265 (CHIR-265)是一种高度选择性的B-Raf和VEGFR2抑制剂，IC50为3-60 nM，也抑制VEGFR2磷酸化， EC50为30 nM。RAF265 是有效的新型BRAF/VEGFR-2抑制剂, 作用于A375M(^V600EBRAF)人黑色素瘤细胞系，降低肿瘤糖代谢和FDG累积。RAF265抑制2-脱氧-2-[¹⁸F]氟代-D-葡萄糖(FDG)累积，这种作用存在剂量依赖性。 RAF265 显著调节糖代谢, 嘧啶代谢,和凋亡通路。

98%

Store at -20℃ for one year（Powder）；Store at 2-4℃ for two weeks；Store at -20℃ for six months after dissolution.

CHIR-265

Ethanol ：10.4 mg/mL (20 mM)

DMSO ：51.8 mg/mL (100 mM)

VEGFR2 ,B-Raf

RAF265 inhibits C-Raf, wild type B-Raf and mutant (V600E) B-Raf. RAF265 effectively block phosphorylation of Raf’s downstream substrates MEK and ERK in cells and also kill melanoma and colorectal cancer cell lines harboring B-Raf mutations independent of PTEN mutation status. Raf kinase inhibition by RAF265 in mutant B-Raf melanoma cell lines causes cell cycle arrest and induces apoptosis, mimicking the effect of Raf RNAi in these cells. RAF265 also potently inhibits the phosphorylation of VEGFR2 and proliferation of VEGF-stimulated hMVEC. In HT29 and MDAMB231 cells, RAF265 shows inhibitory activity with IC20 of 1 to 3 μM and IC50 of 5 to 10 μM, respectively. While RAF265 leads to a significant decrease in clonogenic survival in all tested cell lines, which means that RAF265 induces a dominant effect on clonogenic survival. Addition of RAF265 to RAD001 in HCT116 cells could lead to moderately decreased AKT, S6 protein, and 4EBP1 phosphorylation. Raf265 markedly reduces the protein level of Bcl-2 and great inhibitory in CM- and NCI-H727 cells, while having no effect on the TRAIL susceptibility of BON1 and GOT1 cells. Protein kinase D3 (PRKD3) that when knocked down could enhance cell killing by RAF265 in A2058 melanoma cells, which prevent reactivation of MAPK signaling, induce PARP cleavage, increase caspase activity, interrupt cell-cycle progression, and inhibit colony formation.

RAF265 shows 71% to 72% TVI% (tumor volume inhibition percentage) in HCT116 xenografts at 12 mg/kg. While the combination of RAF265 and RAD001 shows enhanced antitumor activity with increased T10 (time to achieve a relative tumor volume of 10 times the initial tumor volume) and tumor growth delay. The combination of RAD001 and RAF265 also significantly enhances the activation of caspase-3 in HCT116 and MDAMB231 but not in A549 xenografts. RAF265 inhibits FDG (2-deoxy-2-fluoro-d-glucose) accumulation and decreases the tumor volumes in A375M xenografts by orally dosed of 100 mg/kg.

RAF265, a dual BRAF and VEGFR2 inhibitor, prevents osteoclast formation and resorption. Therapeutic implications.
Garcia-Gomezet al. Invest New Drugs. 2012 Jul 7. PMID:

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