生物活性

• 靶点

  B-Raf IC50:9.1nM

  B-Raf (V600E) IC50:5.8nM

  C-Raf IC50:15nM

• 描述The RAS/RAF signaling pathway is an important mediator of tumor cell proliferation and angiogenesis. LY3009120 is a pan RAF inhibitor with IC50 values for 15nM, 5.8nM and 9.1nM for C-Raf, B-Raf^V600E and BRAF-WT (measured by a whole cell-based KiNativ assay), respectively, which can be used to avoid the paradoxical activation of RAF induced by B-Raf^V600E selective inhibitor, like Vemurafenib and Dabrafenib. Treatment with LY3009120 at dose >41nM can dramatically decrease the level of p-ERK in the BRAF WT cell line HCT116, whereas Vemurafenib produces significant paradoxical activation with elevated p-ERK level as doses increase^[1]. Potent inhibition of phosphorylation of both MEK1/2 and ERK1/2 was observed with 1 μM LY3009120 treatment in RKO and HCT 116 cell lines with high basal levels of pMEK1/2 and pERK1/2 at time point 0.5h and 2h, but not in HCT-15 and SW620 cell lines with relative low basal levels of pMEK1/2 and pERK1/2^[2]. Oral administration of LY3009120 at dose of 15 or 30mg/kg b.i.d. caused a dose-dependent tumor growth inhibition in rats bearing BRAF V600E ST019VR PDX tumors^[1].
• 作用机制LY3009120 binds to inactive form of B-Raf (DFG-D_out).^[1][3]
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  human A375 cells	-	Proliferation assay	72 h	Antiproliferative activity against human A375 cells after 72 hrs by resazurin assay, IC50=9.2 nM	25965804
  human A375 cells	-	Function assay	15 mins	Competitive binding affinity to EphA2 in human A375 cells after 15 mins in presence of ATP analogue, IC50=0.02 μM	25965804
  human A375 cells	-	Function assay	15 mins	Competitive binding affinity to BRAF in human A375 cells after 15 mins in presence of ATP analogue, IC50=0.031 μM	25965804

• 更多

• 动物研究
  剂量	Rat: 3 mg/kg - 50 mg/kg[4] (p.o.)
  给药途径	p..o.

• 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
  NCT02014116	Neoplasms Neo... more >>plasm Metastasis Melanoma Carcinoma, Non-Small-Cell Lung Colorectal Neoplasms Collapse <<	Phase 1	Terminated(This trial was term... more >>inated early based on the lack of sufficient clinical efficacy observed.) Collapse <<	-	United States, Arizona ... more >> Pinnacle Oncology Hematology Scottsdale, Arizona, United States, 85258 United States, Massachusetts Massachusetts General Hospital Boston, Massachusetts, United States, 02114 United States, Texas University of Texas MD Anderson Cancer Center Houston, Texas, United States, 77030 Australia For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Nedlands, Australia, 6009 France For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Villejuif, France, 94805 Spain For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Barcelona, Spain, 08035 Collapse <<

• 参考文献

• [1] Henry JR, Kaufman MD, et al. Discovery of 1-(3,3-dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)pyrido[2,3-d] pyrimidin-6-yl)phenyl)urea (LY3009120) as a pan-RAF inhibitor with minimal paradoxical activation and activity against BRAF or RAS mutant tumor cells. J Med Chem. 2015 May 28;58(10):4165-79.

  [2] Vakana E, Pratt S, et al. LY3009120, a panRAF inhibitor, has significant anti-tumor activity in BRAF and KRAS mutant preclinical models of colorectal cancer. Oncotarget. 2017 Feb 7;8(6):9251-9266.

  [3] Roskoski R Jr, et al. Targeting oncogenic Raf protein-serine/threonine kinases in human cancers. Pharmacol Res. 2018 Sep;135:239-258.