生物活性

• 靶点	B-Raf (V600E) IC50:31nM

• 描述The RAS/RAF signaling pathway is an important mediator of tumor cell proliferation and angiogenesis. Among them, B-RAF is the most frequently mutated protein kinase in human cancers. Vemurafenib is a selective inhibitor of B-Raf_V600E mutant with IC50 value of 31nM (measured by enzymatic activity) displays similar potency c-RAF-1 (IC50=48nM), selective against many other kinases, including wild-type B-RAF (IC50=100nM)^[1]. Vemurafenib potently and selectively inhibited proliferation in those melanoma cell lines expressing B-Raf_V600E mutant but not BRAF-WT. Vemurafenib can inhibit p-MEK and p-ERK in B-Raf_V600E- expressing melanoma cell lines, Colo829 and LOX (>0.24μM, for 2h), as well as in WM2664 and WM1341D cell lines (>0.24μM, for 2h), which expresses BRAF_V600D and BRAF_V600R, respectively. However, Vemurafenib showed more variable effect on p-MEK and p-ERK of cell lines that do not express codon 600 BRAF mutations, such as CHL-1 (BRAF_WT) and SK-MEL2 (BRAF_WT), and HMVII (BRAF_G469V) cell line. Vemurafenib possessed good pharmacodynamics as an association between plasma concentration and inhibition of p-MEK and p-ERK can be observed, with the highest plasma concentration (124 μmol/L at 2h) corresponding to the highest mean percent inhibition of phosphorylation (70.5% for MEK and 52% for ERK)^[2]. Oral gavage with Vemurafenib (6/20mg/kg, QD, or 20mg/kg, BID) demonstrated dose-dependent inhibition of tumour growth, with higher exposures (25/75mg/kg, BID) resulting in tumour regression, in COLO205 B-Raf_V600E mutant xenografts^[1].
• 作用机制Vemurafenib is an ATP-competitive inhibitor of mutant BRAF.^[1]
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  8505C (BRAF V600E/V600E)	-	Growth Inhibition Assay	96 h	IC50=57 nM	20149136
  A375	100 μM	Growth Inhibition Assay	96 h	IC50=47 nM	18458053
  A375	10 μM	Apoptosis Assay	-	Promotes apoptotic death	18458053

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• 动物研究
  剂量	Mice: 7.5 mg/kg - 60 mg/kg[4] (p.o.) Rat: 10 mg/kg - 450 mg/kg[5] (p.o.) Dog: 150 mg/kg - 300 mg/kg[5] (p.o.)
  给药途径	p.o.
  动物药代数据	Animal Rats[5] Dogs[5] Dose 50 mg/kg (male, day 91) 150 mg/kg (male, day 29) Administration p.o. p.o. Cmax 29.2 μM 28100 ng/ml Tmax 1 h 9 h AUC0→24h 110.2 μM·h 414000 ng·h/ml

• 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
  NCT02052193	Metastatic Melanoma (Carrying ... more >>BRAF V600 Mutation) Collapse <<	Phase 2	Terminated(Second cohort not o... more >>pened because Simon-Two_Step model failed) Collapse <<	December 2017	Germany ... more >> Department of Dermatology Tuebingen, BW, Germany, 72076 Collapse <<
  NCT01603212	Melanoma	Phase 1 Phase 2	Completed	-	United States, Texas ... more >> University of Texas MD Anderson Cancer Center Houston, Texas, United States, 77030 Collapse <<
  NCT03139513	-	-	Active, not recruiting	December 31, 2018	France ... more >> Centre Hospitalier d'Albi Albi Cedex 9, France, 81013 Hopital Prive D Antony; Dermatologie Antony, France, 92166 Chic Cote Basque Bayonne; Medecine II Bayonne, France, 64109 CHU Besançon - Hôpital Jean Minjoz Besançon Cedex, France, 25030 Hopital Avicenne; Dermatologie Bobigny, France, 93009 CH Fleyriat Bourg en Bresse, France, 01000 CH Metropole de Savoie CHAMBERY Cedex, France, 73011 Chu Estaing; Dermatologie Clermont Ferrand, France, 63003 Hopital Louis Pasteur; Sce Dermatologie Colmar, France, 68024 Centre Georges Francois Leclerc Dijon, France, 21000 Chu Site Du Bocage;Dermatologie Dijon, France, 21079 Centre Hospitalier Le Mans; Dermatologie Le Mans, France, 72037 Hopital Claude Huriez; Sce Dermatologie Lille, France, 59037 CHU de Limoges - Hôpital Dupuytren Limoges, France, 87042 Hopital Timone Adultes; Dermatologie Marseille, France, 13385 Hopital Jacques Monod; Dermatologie Montivilliers, France, 76290 Hopital Saint Eloi; CHU de Montpellier; Svc de Dermatologie Montpellier, France, 34295 CH de Mulhouse Hôpital Emile Muller Mulhouse, France, 68070 Hopital l Archet 2; Ginestriere, Service de; Dermatologie Nice cedex 3, France, 06200 Hopital Cochin; Dermatologie Paris, France, 75006 Groupe Hospitalier Bichat Claude Bernard Paris, France, 75018 CENTRE HOSPITALIER ANNECY-GENEVOIS; Dematologie Pringy, France Centre Eugene Marquis Centre Regional de Lutte Contre Le Cancer Rennes, France, 35000 CHU Rouen - CH C. Nicolle - Clinique dermatologique Rouen, France, 76031 CHU de Saint-Etienne - Hopital Nord Saint Etienne, France, 42055 CHI de Poissy St Germain Saint Germain, France, 07810 Hopital Broussais St Malo Cedex, France, 35403 Pole de Cancerologie Prive Strasbourgeois Strasbourg, France, 67000 Hopital Bel Air Thionville Cedex, France, 57126 Hia Sainte Anne; Medecine Interne Oncologie Toulon, France, 83041 CHU de Toulouse - Hôpital Larrey Toulouse, France, 31059 Centre Hospitalier Valence Valence, France, 26953 Institut Gustave Roussy; Dermatologie Villejuif, France, 94805 Collapse <<

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• 参考文献

• [1] Bollag G, Hirth P, et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature. 2010 Sep 30;467(7315):596-9.

  [2] Yang H, Higgins B, et al. RG7204 (PLX4032), a selective BRAFV600E inhibitor, displays potent antitumor activity in preclinical melanoma models. Cancer Res. 2010 Jul 1;70(13):5518-27.

  [3] Yang H, Higgins B, et al. Antitumor activity of BRAF inhibitor vemurafenib in preclinical models of BRAF-mutant colorectal cancer. Cancer Res. 2012;72(3):779-89.

  [4] Tate SC, Burke TF, et al. Optimising the combination dosing strategy of abemaciclib and vemurafenib in BRAF-mutated melanoma xenograft tumours. Br J Cancer. 2016 Mar 15;114(6):669-79.

  [5] Vemurafenib

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