生物活性

• 靶点	MEK1 IC50:4.2nM

• 描述The Ras-Raf-MEK pathway is overactive in many human cancers, such as melanoma and NSCLC. Cobimetinib, also called as GDC-0973 or RG7420, is a potent and highly selective inhibitor of MEK1 with IC50 value of 4.2 nM (measured by a kinase biochemical assays). Cobimetinib shows strong cellular potency particularly in BRAF or KRAS mutant cancer cell lines (in a detail, 80% of BRAF mutant lines were sensitive to Cobimetinib, 54% of lines carrying oncogenic mutations in KRAS or NRAS were sensitive and 35% of the remaining lines in test were sensitive). Consistent with this, BRAFV600E mutant melanoma tumor models showed higher sensitivity to BRAFV600E mutant melanoma tumor models at dose of 1 - 10 mg/kg, PO, QD x 3. Cobimetinib showed good pharmacodynamics, as treatment of 10 mg/kg dose of Cobimetinib cansuppress p-ERK 75% at 2 - 24 hours in the A375.X1 model^[1]. Cobimetinib combined with vemurafenib was approved by FDA for unresectable or metastatic melanoma with a BRAFV600E or V600K mutation^[2].
• 作用机制Cobimetinib is an ATP-noncompetitive allosteric inhibitor^[3].

• 动物研究
  剂量	Mice[4] (p.o.): 5 mg/kg, 10 mg/kg
  给药途径	p.o.
  动物药代数据	Animal Nude mice[5] Rats[5] Dogs[5] Monkeys[5] Dose 1 mg.kg (i.v.) 3 mg.kg (p.o.) 3 mg.kg (i.v.) 3 mg.kg (p.o.) 3 mg.kg (i.v.) 3 mg.kg (p.o.) 3 mg.kg (i.v.) 3 mg.kg (p.o.) Administration i.v. p.o. i.v. p.o. i.v. p.o. i.v. p.o. Cmax 0.184 ng/ml (p.o.) 0.193 ± 0.125 ng/ml (p.o.) 0.843 ± 0.214 ng/ml (p.o.) 0.050 ± 0.010 ng/ml (p.o.) T1/2 3.92 h (i.v.) 13.3 ± 2.5 h (i.v.) 9.19 ± 1.57 h (i.v.) 10.3 ± 3.3 h (i.v.) F 53.9% (p.o.) 69.0 ± 8.0% (p.o.) 69.1 ± 11.7% (p.o.) 19.6 ± 3.5% (p.o.) Vss 34.6 ± 8.5 l/kg (i.v.) 3.99 ± 0.58 l/kg (i.v.) 29.6 ± 8.5 l/kg (i.v.) Tmax 0.250 h (p.o.) 3.50 h (p.o.) 2.67 h (p.o.) 2.00 h (p.o.) Vss 9.40 l/kg (i.v.) AUCinf 0.935 ng·h/ml (i.v.) 1.51 ng·h/ml (p.o.) 2.32 ± 0.18 ng·h/ml (i.v.) 1.59 ± 0.10 ng·h/ml (p.o.) 17.1 ± 1.0 ng·h/ml (i.v.) 11.9 ± 2.6 ng·h/ml (p.o.) 3.34 ± 0.87 ng·h/ml (i.v.) 0.64 ± 0.12 ng·h/ml (p.o.) CL 33.5 ml/min/kg (i.v.) 37.8 ± 7.2 ml/min/kg (i.v.) 5.53 ± 0.31 ml/min/kg (i.v.) 29.6 ± 8.5 ml/min/kg (i.v.)