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Agerafenib hydrochloride  ≥98%

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包装规格：5mg 25mg in glass bottle
产品描述：基本信息 产品编号： A12285 产品名称： Agerafenib hydrochloride CAS: 1227678-26-3   储存条件 粉末 -20℃ 四年     分子式： C24H23ClF3N5O5 溶于液体     分子量 553.92     化学名：  1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea hydrochloride   生物活性 产品描述 一种口服高效的BRAFV600E抑制剂 靶点 BRafV600E 14nM(Kd) Braf 36nM(Kd) CRAF 39nM(Kd) c-Kit 2nM(Kd) Ret 2nM(Kd) LCK 2nM(Kd) Abl-1 3nM(Kd) VEGFR- 28nM(Kd) CSF-1R 9nM(Kd) EPHA2 14nM(Kd) EGFR 22nM(Kd) c-Met 513nM(Kd) JAK-2 4700nM(Kd) MEK-1 7100nM(Kd) MEK-2 8300nM(Kd)   体外研究 Agerafenib (CEP-32496) exhibits high potency against several BRAFV600E-dependent cell lines and selective cytotoxicity for tumor cell lines expressing mutant BRAFV600Eversus those containing wild-type BRAF. Agerafenib (CEP-32496) exhibits potent binding (BRAFV600E Kd=14nM) and cellular activity (pMEK IC50=82nM and A375 proliferation IC50=78nM), with activity in the proliferation assay. CEP-32496 also exhibits a favorable CYP450 inhibition profile, with measured IC50 values greater than 10μM versus the CYP1A2, CYP2C9, CYP2D6, and CYP3A4 isoforms and an IC50=3.4μM versus CYP2C19 体内研究 Oral administration of Agerafenib (CEP-32496) to Colo-205 tumor xenograft-bearing mice results in significant inhibition of pMEK in tumor cell lysates. For instance, a single 30 mg/kg (po) dose of Agerafenib (CEP-32496) leads to a 50 and 75% inhibition of normalized pMEK in tumor lysates at the 2 and 6 h postdose time point, respectively (p<0.03), while a 55 mg/kg (po) dose resulted in a 75% to 57% (p<0.03) inhibition of pMEK at 2 through 10 h post administration, with normalization to baseline by 24 h. Agerafenib (CEP-32496) exhibits an exceptional PK profile in mouse, dog, and cynomolgus monkey. Administration of Agerafenib (CEP-32496) to beagle dogs (single dose of 1 mg/kg iv and 10 mg/kg po) results in low clearance (CL=5.0 (mL/min)/kg) and excellent bioavailability (%F=100). Similarly, in cynomolgus monkey, the administration of Agerafenib (CEP-32496) (single dose of 1 mg/kg iv and 10 mg/kg po) leads to high oral exposure due to low clearance (CL=6.7 mL/min/kg) and excellent bioavailability (%F=100)   推荐实验方法(仅供参考) Cell Assay A375 cells are seeded at 10,000 cells per well in DMEM with 10% fetal calf serum and allowed to attach. The cells are washed with PBS and switched to DMEM with 0.5% of serum and incubated overnight. The test compounds (e.g., Agerafenib (CEP-32496); 10μM) are then added at various concentrations with a final DMSO concentration of 0.5% and incubated for 72 h. At the end of incubation, a Cell Titer Blue is added per instructions, and incubation is continued for 3 h. Remaining viable cells are quantified by measuring the strength of the fluorescence signal using SoftMax Pro (excitation at 560 nm and emission at 590 nm). IC50 values are derived using a 9-point curve and are presented as mean values from experiments performed in duplicate Animal Administration Mice Six to eight week old athymic nu/nu nude mice (20-25 g) are inoculated subcutaneously with Colo-205 tumor cells (1×106/mouse) in the right flank. Upon reaching an average tumor volume of 150-200 mm3 (10-12 days post implantation), animals are randomized into treatment groups (n=10 mice/group). Each group is dosed orally for 14 days with either vehicle only (22% HPβCD) or with Agerafenib (CEP-32496) at 10, 30, or 100 mg/kg twice daily (BID), and each dose of drug is given in a volume of 0.1 mL per 20 g of body weight, adjusted for the body weight of the animal. Tumor volumes are measured three times weekly using vernier calipers, and volumes are calculated
保存条件：-20℃

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