生物活性

• 靶点

  B-Raf IC50:22nM

  C-Raf IC50:6nM

  VEGFR2 IC50:90nM

• 描述The RAS/RAF signaling pathway is an important mediator of tumor cell proliferation and angiogenesis. Sorafenib is a multitargeted inhibitor with IC50 values of 6nM, 22nM and 38nM for Raf-1, wt-BRAF and BRAF-V599E mutant, respectively, as well as less potent to mVEGFR2, mVEGFR3, mPDGFRβ, FLT3, c-Kit, VEGFR2 and FGFR1 with IC50 values of 15nM, 20nM, 57nM, 58nM, 68nM, 90nM and 580nM (measured by kinase assays), respectively. Sorafenib inhibited activation of the RAF/MEK/ERK pathway at concentration below 15μM, performing by suppressing p-Erk, in most of cell lines tested (like MDA-MB-231. Mia PaCa 2, HCT 116 and HT-29) independent of which mutation caused aberrant activation of the RAS/RAF pathway. Sorafenib targeted receptor tyrosine kinases and inhibited autophosphorylation of VEGFR-2 and PDGFR-β induced by VEGF165 (30ng/ml) in HUVECs/ NIH 3T3 cells and PDGF BB (10ng/ml) in HAoSMCs, respectively. Oral treatment with Sorafenib, at dose of 7.5-60mg/kg daily for 9 days, illustrated a spectrum of antitumor efficacy in a representative panel of tumor xenograft models in a dose-dependent manner, including MDA-MB-231, Colo-205, HT-29, DLD-1, NCI-H460 and A549. Sorafenib showed significant tumor angiogenesis activity, performing as daily oral administration of 30 or 60 mg/kg Sorafenib produced 50-80% inhibition of microvessel area and microvessel density compared with vehicle group in HT-29 tumors^[1].
• 作用机制Sorafenib is a multitargeted ATP-competitive inhibitor.^[1]
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  697	-	Growth Inhibition Assay	-	IC50=7.05989 μM	SANGER
  A101D	-	Growth Inhibition Assay	-	IC50=21.3752 μM	SANGER
  A253	-	Growth Inhibition Assay	-	IC50=34.2296 μM	SANGER

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• 动物研究
  剂量	Mice: 30 mg/kg, 60 mg/kg[4] (p.o.), 10 mg/kg - 100 mg/kg[2] (p.o.) Woodchucks: 2.5 mg/kg, 5 mg/kg[5] (p.o.)
  给药途径	p.o.
  动物药代数据	Animal Mice[6] Rats[6] Dogs[6] Dose 5 mg/kg (i.v. or p.o.) 5.63 mg/kg (i.v.) 4.85 mg/kg (p.o.) 5.77 mg/kg (i.v.) 5.65 mg/kg (p.o.) Administration i.v. p.o. i.v. p.o. i.v. p.o. F 78.6% (p.o.) 79.1% (p.o.) 59.9% (p.o.) AUC0→inf 33.30 mg·h/l (i.v.) 19.54 mg·h/l (p.o.) T1/2 6.53 h (i.v.) 5.77 h (p.o.) 9.33 h (i.v.) 8.86 h (p.o.) 4.33 h (i.v.) 3.59 h (p.o.) Tmax 1.0 (p.o.) 1.74 (p.o.) 1.59 (p.o.) MRT 4.55 h (i.v.) 14.72 h (p.o.) 14.87 h (i.v.) 16.08 h (p.o.) 5.83 h (i.v.) 5.5 h (p.o.) Vz/F 1.59 L/kg (p.o.) 0.71 L/kg (p.o.) Cmax 13.17 mg/l (i.v.) 1.15 mg/l (p.o.) 8.35 mg/l (i.v.) 3.65 mg/l (p.o.) CL 0.15 L/h/kg (i.v.) 0.19 L/h/kg (p.o.) 0.04 L/h/kg (i.v.) 0.06 L/h/kg (p.o.) 0.13 L/h/kg (i.v.) 0.21 L/h/kg (p.o.) Vz/f 1.09 L/kg (p.o.) Vss 0.68 L/kg (i.v.) 0.65 L/kg (i.v.) 0.74 L/kg (i.v.) AUC 24.33 mg·h/l (i.v.) 19.13 mg·h/l (p.o.) 94.16 mg·h/l (i.v.) 64.26 mg·h/l (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
  NCT03565536	Thyroid Cancer, Anaplastic	Phase 2	Recruiting	October 30, 2019	China, Fujian ... more >> Fujian Medical University Union Hospital Recruiting FuZhou, Fujian, China, 350001 Contact: bo wang, md    13705947900    wangbo@fjmu.edu.cn Collapse <<
  NCT00984425	Solid Tumors	Phase 1	Completed	-	Italy ... more >> Istituto Clinco Humanitas Rozzano, Milano, Italy, 20089 Collapse <<
  NCT01259193	Hepatocellular Carcinoma	Phase 2	Unknown	July 2012	China, Shanghai ... more >> Liver Cancer Institute Recruiting Shanghai, Shanghai, China, 200032 Contact: Zheng-Gang Ren, Ph.D    0086-021-64041990 ext 2137    ren.zhenggang@zs-hospital.sh.cn    Contact: Lan Zhang, Master    0086-021-64041990 ext 2171    zhang.lan@zs-hospital.sh.cn    Principal Investigator: Zheng-Gang Ren, Ph.D          Sub-Investigator: Jubo Zhang, PhD Collapse <<

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• 参考文献

• [1] Wilhelm SM, Carter C, et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004 Oct 1;64(19):7099-109.

  [2] Huynh H, Ngo VC, et al. Sorafenib and rapamycin induce growth suppression in mouse models of hepatocellular carcinoma. J Cell Mol Med. 2009;13(8B):2673-83.

  [3] El-Ashmawy NE, Khedr EG, et al. Sorafenib effect on liver neoplastic changes in rats: more than a kinase inhibitor. Clin Exp Med. 2017;17(2):185-191.

  [4] Kuczynski EA, Lee CR, et al. Effects of Sorafenib Dose on Acquired Reversible Resistance and Toxicity in Hepatocellular Carcinoma. Cancer Res. 2015 Jun 15;75(12):2510-9.

  [5] Iyer RV, Maguire O, et al. Dose-Dependent Sorafenib-Induced Immunosuppression Is Associated with Aberrant NFAT Activation and Expression of PD-1 in T Cells. Cancers (Basel). 2019 May 16;11(5). pii: E681.

  [6] Nexavar

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