生物活性

• 靶点	B-Raf (V600E) IC50:0.8nM

• 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. Dabrafenib is a potent, selective and efficacious inhibitor of B-Raf^V600E with IC₅₀ value of 0.7 nM, and less potent to B-Raf and C-Raf with IC₅₀ values of 5.2 nM and 6.3 nM (measured by enzymatic activity), respectively. Consistent with the in vitro kinase assay, Dabrafenib displayed compelling inhibitory on p-ERK in SKMEL28 cells with IC₅₀ value of 4 nM, as well as on cell proliferation of B-Raf^V600E-driven melanoma lines such as SKMEL28 and A375P F11 (IC₅₀=3 nM and 8 nM, respectively) and colorectal carcinoma line Colo205 (IC₅₀=7 nM). Meanwhile, Dabrafenib had a minimal effect on cells with wild-type B-Raf (HFF IC₅₀=3.0 μM) and in tumor cells not harboring the activating B-Raf^V600E mutation. Oral administration of Dabrafenib at doses of 0.1, 1, 10, and 100 mg/kg once daily for 14 days dose-dependently reduce tumor growth with notable pharmacodynamic response, measured by pERK levels after a single oral dose, in CD1 nu/nu mice bearing A375P F11 (B-Raf^V600E) tumors. Dabrafenib is currently in phase III clinical development for the treatment of activating B-Raf mutant tumors^[1].
• 作用机制Dabrafenib binding to BRAF is ATP-competitive.^[2]
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  22Rv1	10 μM	Growth Inhibition Assay	72 h	IC50=10 μM	23844038
  647-V	10 μM	Growth Inhibition Assay	72 h	IC50=10 μM	23844038
  786-O	10 μM	Growth Inhibition Assay	72 h	IC50=10 μM	23844038

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• 动物研究
  剂量	Mice: 0.3 mg/kg - 100 mg/kg[2] (p.o.) Dog: 1 mg/kg - 50 mg/kg[3] (p.o.) Rat: 5 mg/kg - 200 mg/kg[3] (p.o.)
  给药途径	p.o.
  动物药代数据	Animal Rats[3] Dose 20 mg/kg Administration p.o. Cmax 9.4 - 11.8 µg/ml Tmax 0.5 - 1 h AUC0→t 19.2 - 24.3 µg·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
  NCT01512251	BRAF Mutant Metastatic Melanom... more >>a Collapse <<	Phase 1 Phase 2	Completed	-	United States, California ... more >> University of California, San Francisco San Francisco, California, United States, 94115 Collapse <<
  NCT01512251	-	-	Completed	-	-
  NCT02089724	-	-	Recruiting	April 2019	United States, New York ... more >> Memorial Sloan Kettering Cancer Center Recruiting New York, New York, United States, 10065 Contact: Eli L. Diamond, MD, PhD       diamonel@mskcc.org    Principal Investigator: Eli L. Diamond, MD, PhD          Sub-Investigator: Omar Abdel-Wahab, MD          France AP-HP, Groupe Hospitalier Pitié-Salpêtrière Recruiting Paris, France, 75013 Contact: Julien Haroche, MD, PhD    +33 1 42 17 80 37    julien.haroche@psl.aphp.fr    Contact: Fleur Cohen Aubart, MD, PhD    +33 1 42 17 82 42    fleur.cohen@psl.aphp.fr    Principal Investigator: Julien Haroche, MD, PhD          Sub-Investigator: Fleur Cohen Aubart, MD, PhD          Sub-Investigator: Zahir Amoura, MD, MSc Collapse <<

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• 参考文献

• [1] Rheault TR, Stellwagen JC, et al. Discovery of Dabrafenib: A Selective Inhibitor of Raf Kinases with Antitumor Activity against B-Raf-Driven Tumors. ACS Med Chem Lett. 2013 Feb 7;4(3):358-62.

  [2] King AJ, Arnone MR, et al. Dabrafenib; preclinical characterization, increased efficacy when combined with trametinib, while BRAF/MEK tool combination reduced skin lesions. PLoS One. 2013 Jul 3;8(7):e67583.

  [3] Tafinlar