生物活性

• 靶点

  Axl IC50:7nM

  c-Kit IC50:4.6nM

  c-Met IC50:1.3nM

  c-RET IC50:4nM

  FLT3 IC50:11.3nM

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• 描述The inhibition of VEGF/VEGFR, as well as HGF/c-Met pathway contributes to tumor growth, angiogenesis, invasiveness and metastasis in preclinical studies. Cabozantinib is a potent VEGFR2 inhibitor with IC50 value of 0.035nM, as well as shows inhibitory effect on c-Met, Ret, Kit, Flt-1/3/4, Tie2, and AXL with IC50 values of 1.3nM, 4nM, 4.6nM, 12nM/11.3nM/6nM, 14.3nM and 7nM (measured by kinase activity), respectively^[1]. Treatment with Cabozantinib dose-dependently inhibited HGF-induced p-Met at concentration>0.05μM and its downstream p-AKT at concentration>0.1μM in MPNST724 cells, as well as at concentration of 1μM in HUVECs, 0.5μM in ST88 and STS26T cells. The inhibition of VEGFR-2 by Cabozantinib can be observed, as decreased p-VEGFR2, at concentration>0.5μM in HUVECs. Cabozantinib inhibited HGF-induced MPNST cell migration and invasion at 0.5μM for 4h. As prediction by inhibition of Cabozantinib on VEGFR2 and c-Met, Cabozantinib showed potent anti-angiogenesis effect in vivo. The in vivo gel-foam suggested that angiogenesis induced by HGF, VEGF or both decreased (measured based on CD31) by administration of 30mg/kg Cabozantinib for 10 days^[2]. Oral treatment with Cabozantinib for 7 days reduced tumor vascularity by 67% at 3mg/kg and by 83% at 30mg/kg in RIP-Tag2 tumors^[1].
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  E98NT	0.01-10 μM	Growth Inhibition Assay	-	IC50=89 nM	23484006
  H441	-	Growth Inhibition Assay	-	IC50=21700 nM	21926191
  H69	-	Growth Inhibition Assay	-	IC50=20200 nM	21926191

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• 动物研究
  动物给药方法	Mice: min = 30 mg/kg[3], max = 100 mg/kg[4]
  剂量	Mice: 30 mg/kg[5] (i.p.); 30 mg/kg[6] (p.o.)
  给药途径	i.p., p.o.
  动物药代数据	Animal Rats[7] Monkeys[7] Dose 5 mg/kg 3 mg/kg [formulation: EPW(ethanol:PEG400:water=5:45:50)] Administration i.v. or p.o. i.v. or p.o. F 111% (p.o.) 73% (p.o.) AUC0-inf 259 μM·h (i.v.) 288 μM·h (p.o.) T1/2 10.9 h (i.v.) 14.1 h (p.o.) 3.92 h (i.v.) 4.18 h (p.o.) AUC0→inf 8.65 μM·h (i.v.) 6.33 μM·h (p.o.) Tmax 0.25 h (i.v.) 4.0 h (p.o.) 0.08 h (i.v.) 3.0 h (p.o.) CL 0.038 L/kg/h (i.v.) 0.64 L/kg/h (i.v.) Cmax 18.7 μM (i.v.) 14.6 μM (p.o.) 2.51 μM (i.v.) 0.98 μM (p.o.) Vdss 0.6 L/kg (i.v.) 2.67 L/kg (i.v.) AUC0→t 196 μM·h (i.v.) 192 μM·h (p.o.) 8.74 μM·h (i.v.) 6.46 μM·h (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
  NCT03696407	-	-	Not yet recruiting	May 31, 2019	United Kingdom ... more >> Royal Sussex County Hospital Not yet recruiting Brighton, United Kingdom, BN2 5BE Addenbrooke's Hospital Not yet recruiting Cambridge, United Kingdom, CB2 0QQ Beatson West of Scotland Cancer Centre Not yet recruiting Glasgow, United Kingdom, G12 0YN The Christie Hospital Not yet recruiting London, United Kingdom, EC1A 7BE The Christie Hospital Not yet recruiting Manchester, United Kingdom, M20 4BX Collapse <<
  NCT00704730	Thyroid Cancer	Phase 3	Unknown	December 2015	-
  NCT00704730	-	-	Unknown	-	-

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• 参考文献

• [1] You WK, Sennino B, et al. VEGF and c-Met blockade amplify angiogenesis inhibition in pancreatic islet cancer. Cancer Res. 2011;71(14):4758-68.

  [2] Torres KE, Zhu QS, et al. Activated MET is a molecular prognosticator and potential therapeutic target for malignant peripheral nerve sheath tumors. Clin Cancer Res. 2011;17(12):3943-55.

  [3] Nguyen HM, Ruppender N, et al. Cabozantinib inhibits growth of androgen-sensitive and castration-resistant prostate cancer and affects bone remodeling. PLoS One. 2013;8(10):e78881.

  [4] Navis AC, Bourgonje A, et al. Effects of dual targeting of tumor cells and stroma in human glioblastoma xenografts with a tyrosine kinase inhibitor against c-MET and VEGFR2. PLoS One. 2013;8(3):e58262.

  [5] Haider MT, Hunter KD, et al. Rapid modification of the bone microenvironment following short-term treatment with Cabozantinib in vivo. Bone. 2015 Dec;81:581-592.

  [6] Yang S, Zhang X, et al. Cabozantinib induces PUMA-dependent apoptosis in colon cancer cells via AKT/GSK-3β/NF-κB signaling pathway. Cancer Gene Ther. 2019 Jun 11.

  [7] XL 184

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