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].
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  human COLO205 cells	-	Function assay	-	Inhibition of B-raf V600E mutant in human COLO205 cells assessed as reduction of ERK1/ERK2 phosphorylation, IC50=1.8 nM	22315332
  human COLO205 cells	-	Proliferation assay	-	Antiproliferative activity against human COLO205 cells expressing B-raf V600E mutant, IC50=8 nM	22315332
  human MDA-MB-231T cells	-	Function assay	1 h	Inhibition of MEK-mediated ERK T202/Y204 phosphorylation in human MDA-MB-231T cells after 1 hr by immunoblotting， IC50=0.2 nM	24900486

• 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.)

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT03273153	Advanced BRAFV600 Wild-type Me... more >>lanoma Collapse <<	Phase 3	Recruiting	September 17, 2024	-
  NCT03297606	Lymphoma, Non-Hodgkin ... more >> Multiple Myeloma Advanced Solid Tumors Collapse <<	Phase 2	Recruiting	September 2021	Canada, British Columbia ... more >> BCCA - Vancouver Cancer Centre Recruiting Vancouver, British Columbia, Canada, V5Z 4E6 Contact: Daniel John Renouf    604 877-6000 ext 672357       Canada, Ontario London Regional Cancer Program Recruiting London, Ontario, Canada, N6A 5W9 Contact: Stephen Welch    519 685-8640       Ottawa Hospital Research Institute Recruiting Ottawa, Ontario, Canada, K1H 8L6 Contact: John Hilton    613 737-7700 ext 70179       University Health Network Recruiting Toronto, Ontario, Canada, M5G 2M9 Contact: Lillian Siu    416 946-2911       Canada, Quebec The Jewish General Hospital Recruiting Montreal, Quebec, Canada, H3T 1E2 Contact: Cristiano Ferrario    514 398-8307 Collapse <<
  NCT01506973	Advanced Adenocarcinoma ... more >> Metastatic Adenocarcinoma Collapse <<	Phase 1 Phase 2	Active, not recruiting	-	United States, Pennsylvania ... more >> Abramson Cancer Center of the University of Pennsylvania Philadelphia, Pennsylvania, United States, 19104 Collapse <<

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• 参考文献

• [1] Hoeflich KP, Merchant M, et al. Intermittent administration of MEK inhibitor GDC-0973 plus PI3K inhibitor GDC-0941 triggers robust apoptosis and tumor growth inhibition. Cancer Res. 2012 Jan 1;72(1):210-9.

  [2] Cobimetinib: A Novel MEK Inhibitor for Metastatic Melanoma

  [3] Rice KD, Aay N, et al. Novel Carboxamide-Based Allosteric MEK Inhibitors: Discovery and Optimization Efforts toward XL518 (GDC-0973). ACS Med Chem Lett. 2012 Apr 9;3(5):416-21.

  [4] Kawaguchi K, Igarashi K, et al. MEK inhibitors cobimetinib and trametinib, regressed a gemcitabine-resistant pancreatic-cancer patient-derived orthotopic xenograft (PDOX). Oncotarget. 2017 Jul 18;8(29):47490-47496.

  [5] Choo EF, Belvin M, et al. Preclinical disposition of GDC-0973 and prospective and retrospective analysis of human dose and efficacy predictions. Drug Metab Dispos. 2012 May;40(5):919-27.

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