生物活性

• 描述B-Raf protein is a key mediator in the MAPK signaling pathway that involved in the pathogenesis of multiple cancers. An important V600E mutation has been shown to cause constitutive B-Raf activation. RAF265 is an oral molecule inhibitor of both mutant BRAF^V600E and VEGFR2 with EC₅₀ values of 0.14 μM and 0.19 μM, respectively^[5]. The IC₅₀ values of RAF265 against of BRAF^V600E, wild-type BRAF, VEGFR, and C-RAF were 0.5, 70, 20 and 19μM, respectively^[6]. In HT29 and MDAMB231 cells, RAF265 inhibited cell viability with IC₂₀ values of 1-3μM and IC₅₀ values of 5-10μM. In A549 and HCT116 cells, the IC20₂₀ values of RAF265 were 1μM for both cell lines, but the IC₅₀ values were more than 10μM. Additionally, treatment with RAF265 at the concentrations of 1-10μM decreased MEK phosphorylation in BRAF-mutated cell lines. In HCT116, HT29, and MDAMB231 cell lines, increasing doses of RAF265 also decreased the phosphorylation of S6 ribosomal protein. In mice inoculated with HCT116 cancer cells, the time to achieve a relative 10 times of the initial tumor volume was 25 days in the RAF265 group (12 mg/kg, once per day), compared to 20 days in the control group. The combination of RAF265 and RAD001 at a dose of 12 mg/kg/d delayed the tumor growth for 5 days ^[7].
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  A375 cells	-	Proliferation assay	-	Antiproliferative activity against human A375 cells harboring B-RAF V600E mutant, IC50=0.04 μM	26396681
  human Malme-3M cells	-	Function assay	-	Inhibition of B-RAF V600E mutant in human Malme-3M cells assessed as phosphorylation of ERK, IC50=0.04 μM	26396681
  SK-MEL-28 cells	-	Function assay	-	Inhibition of B-RAF V600E mutant in human SK-MEL-28 cells assessed as phosphorylation of ERK, IC50=0.14 μM	26396681

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• 动物研究
  剂量	Mice: 10 mg/kg - 100 mg/kg[3] (p.o., q2d); 0.2 mg/kg, 10 mg/kg - 20 mg/kg[4] (i.p.)
  给药途径	p.o., i.p.
  动物药代数据	Animal Mice[3] Rats[3] Dogs[3] Monkeys[3] Dose 5 mg/kg (i.v.) 30 mg/kg (p.o.) 5 mg/kg (i.v.) 20 mg/kg (p.o.) 1.25 mg/kg (i.v.) 5 mg/kg (p.o.) 1 mg/kg (i.v.) 5 mg/kg (p.o.) Administration i.v. p.o. i.v. p.o. i.v. p.o. i.v. p.o. F 0.51 >95% 0.35 0.28 T1/2 41 h 46 h 27 h 27 h AUC∞ 4300 μM·h (p.o.) 450 μM·h (p.o.) 35 μM·h (p.o.) 48 μM·h (p.o.) CL 0.1 ml/min/kg 0.9 ml/min/kg 0.8 ml/min/kg 1.5 ml/min/kg Vss 0.5 L/kg 3.3 L/kg 1.9 L/kg 2.9 L/kg

• 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
  NCT01352273	Advanced Solid Tumors	Phase 1	Completed	-	United States, Florida ... more >> H. Lee Moffitt Cancer Center & Research Institute Moffitt 4 Tampa, Florida, United States, 33612 United States, Oregon Oregon Health & Science University OHSU 3 Portland, Oregon, United States, 97239 United States, Utah University of Utah / Huntsman Cancer Institute Huntman 2 Salt Lake City, Utah, United States, 84103 Canada, Alberta Novartis Investigative Site Edmonton, Alberta, Canada, T6G 1Z2 Canada, Quebec Novartis Investigative Site Montreal, Quebec, Canada, H3T 1E3 Norway Novartis Investigative Site Oslo, Norway, NO-0379 Spain Novartis Investigative Site Madrid, Spain, 28050 Switzerland Novartis Investigative Site Zürich, Switzerland, 8091 Collapse <<
  NCT00304525	Metastatic Melanoma	Phase 2	Completed	-	United States, Colorado ... more >> University of Colorado Univ.ofColoradoCancerCenter Aurora, Colorado, United States, 80045 United States, Georgia Georgia Regents University Cancer Clinical Research Unit Augusta, Georgia, United States, 30912 United States, Maryland Sidney Kimmel Comprehensive Cancer Center/Johns Hopkins Med. Medical Oncology Baltimore, Maryland, United States, 21231 United States, Massachusetts Massachusetts General Hospital Dept of Cancer for Melanoma Boston, Massachusetts, United States, 02114 Dana Farber Cancer Institute DFCI Boston, Massachusetts, United States, 02115 Beth Israel Deaconess Medical Center Dept.ofBethIsraelDeaconess(3) Boston, Massachusetts, United States, 02215 United States, Pennsylvania University of Pennsylvania Health System Dept of Hospital of UnivofPenn Philadelphia, Pennsylvania, United States, 19104 University of Pittsburgh Cancer Institute Dept of Hillman Cancer Center Pittsburgh, Pennsylvania, United States, 15232 United States, Tennessee Vanderbilt University Medical Center Dept. of Cancer Center Nashville, Tennessee, United States, 37232 United States, Texas University of Texas/MD Anderson Cancer Center Onc. Dept, Houston, Texas, United States, 77030-4009 Switzerland Novartis Investigative Site Zürich, Switzerland, 8091 Collapse <<

• 参考文献

• [1] Mordant P, Loriot Y, et al. Dependence on phosphoinositide 3-kinase and RAS-RAF pathways drive the activity of RAF265, a novel RAF/VEGFR2 inhibitor, and RAD001 (Everolimus) in combination. Mol Cancer Ther. 2010 Feb;9(2):358-68.

  [2] Zitzmann K, de Toni E, et al. The novel Raf inhibitor Raf265 decreases Bcl-2 levels and confers TRAIL-sensitivity to neuroendocrine tumour cells. Endocr Relat Cancer. 2011 Mar 21;18(2):277-85.

  [3] Williams TE, Subramanian S, et al. Discovery of RAF265: A Potent mut-B-RAF Inhibitor for the Treatment of Metastatic Melanoma. ACS Med Chem Lett. 2015 Aug 3;6(9):961-5.

  [4] Chow AK, Cheng NS, et al. Preclinical analysis of the anti-tumor and anti-metastatic effects of Raf265 on colon cancer cells and CD26(+) cancer stem cells in colorectal carcinoma. Mol Cancer. 2015 Apr 11;14:80.

  [5] Huang T, Karsy M, Zhuge J, Zhong M, Liu D. B-Raf and the inhibitors: from bench to bedside. J Hematol Oncol. 2013 Apr 25;6:30. doi: 10.1186/1756-8722-6-30. PMID: 23617957; PMCID: PMC3646677.

  [6] Williams TE, Subramanian S, Verhagen J, McBride CM, Costales A, Sung L, Antonios-McCrea W, McKenna M, Louie AK, Ramurthy S, Levine B, Shafer CM, Machajewski T, Renhowe PA, Appleton BA, Amiri P, Chou J, Stuart D, Aardalen K, Poon D. Discovery of RAF265: A Potent mut-B-RAF Inhibitor for the Treatment of Metastatic Melanoma. ACS Med Chem Lett. 2015 Aug 3;6(9):961-5. doi: 10.1021/ml500526p. PMID: 26396681; PMCID: PMC4569875.

  [7] Mordant P, Loriot Y, Leteur C, Calderaro J, Bourhis J, Wislez M, Soria JC, Deutsch E. Dependence on phosphoinositide 3-kinase and RAS-RAF pathways drive the activity of RAF265, a novel RAF/VEGFR2 inhibitor, and RAD001 (Everolimus) in combination. Mol Cancer Ther. 2010 Feb;9(2):358-68. doi: 10.1158/1535-7163.MCT-09-1014. Epub 2010 Feb 2. PMID: 20124452.

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