生物活性

• 靶点

  c-Kit IC50:1.7nM

  PDGFRβ IC50:1.6nM

  VEGFR1 IC50:0.1nM

  VEGFR2 IC50:0.2nM

  VEGFR3 IC50:0.1nM-0.3nM

• 描述VEGF/VEGFR (vascular endothelial growth factor/vascular endothelial growth factor receptor) pathway plays a key role in tumor angiogenesis by promotion of vascular and lymphatic endothelial, as well as survival, and invasion, thus resulting in neovascularization, tumor growth and metastasis. Axitinib is a selective and potent VEGFR inhibitor with IC50 values of 0.1nM, 0.18nM, 0.2nM and 0.1nM-0.3nM for VEGFR1/FLT1, VEGFR2/Flk1, VEGFR2/KDR and VEGFR3, as well as less potent to PDGFRβ, Kit and PDGFRα with IC50 value of 1.6nM, 1.7nM and 5.0nM (measured by enzymatic assays), respectively. Treatment with Axitinib at concentration ranging in 1-300nM for 45min caused inhibition on downstream signaling induced by VEGF (50ng/ml), including p-AKT (>1nM), p-eNOS (>1nM) and p-ERK (>10nM), in a dose-dependent manner in HUVECs. Axitinib inhibited dose dependently VEGF-stimulated (20ng/ml) growth of HUVECs (for 3 days) with IC50 of 0.17nM, as well as blocked the sprouting and tube formation of human microvascular endothelial cell spheroids at 3, 6, 12.5, 25, and 50nM (for 7 days). Oral treatment with Axitinib at dose ranging in 3-150mg/kg showed dose-dependently tumor growth inhibition in MV522 tumor model, with reduced Ki-67 (marked cell division) and increased caspase-3 in the tumor. Axitinib also enhanced antitumor efficacy of chemotherapeutic agents, including docetaxel in LLC and human breast cancer models, carboplatin in a human ovarian cancer model and gemcitabine in a human pancreatic cancer model, as well as produced significant antimetastasis activity combined with bevacizumab in M24met model^[1].
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  22RV1	-	Growth Inhibition Assay	-	IC50=17.5884 μM	SANGER
  23132-87	-	Growth Inhibition Assay	-	IC50=12.0821 μM	SANGER
  5637	-	Growth Inhibition Assay	-	IC50=29.6421 μM	SANGER

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• 动物研究
  剂量	Mice: min = 25 mg/kg[2], max = 35 mg/kg[3]
  给药途径	p.o., i.p.

• 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
  NCT00692341	Hepatic Insufficiency	Phase 1	Completed	-	United States, Florida ... more >> Pfizer Investigational Site Miami, Florida, United States, 33169 Pfizer Investigational Site Orlando, Florida, United States, 32809 Collapse <<
  NCT03386929	Non-small Cell Lung Cancer Met... more >>astatic Non-Small Cell Lung Cancer Stage IIIB Collapse <<	Phase 1 Phase 2	Recruiting	December 2022	United States, California ... more >> UCSD Moores Cancer Center Recruiting La Jolla, California, United States, 92093 Contact: Sarah MOORE       sam055@ucsd.edu    Principal Investigator: Lyudmila BAZHENOVA, MD          United States, South Dakota Avera Cancer Center Recruiting Sioux Falls, South Dakota, United States, 57105 Contact: Martha LANG       Martha.lang@avera.org    Principal Investigator: Benjamin SOLOMON, MD          France Centre Léon Bérard Recruiting Lyon, France, 69008 Contact: Séverine LAURENT       severine.laurent@lyon.unicancer.fr    Principal Investigator: Pierre SAINTIGNY, MD          Israel Chiam Sheba Medical Center Recruiting Ramat Gan, Israel, 5265601 Contact: Yona GILADY       yona.gilady@sheba.health.gov.il    Principal Investigator: Jair BAR, MD          Luxembourg Centre Hospitalier Luxembourg Recruiting Luxembourg, Luxembourg, 1210 Contact: Lucile PERNOT       lucile.pernot@lih.lu    Principal Investigator: Guy BERCHEM, MD          Spain Vall Hebron Institute of Oncology Recruiting Barcelona, Spain, 08035 Contact: LLuisa CARBONELL       llcarbonell@vhio.net    Principal Investigator: Enriqueta Felip, MD Collapse <<
  NCT00389441	Thyroid Neoplasms	Phase 2	Completed	-	-

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• 参考文献

• [1] Hu-Lowe DD, Zou HY, et al. Nonclinical antiangiogenesis and antitumor activities of axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endothelial growth factor receptor tyrosine kinases 1, 2, 3. Clin Cancer Res. 2008;14(22):7272-83.

  [2] Du Four S, Maenhout SK, et al. Axitinib increases the infiltration of immune cells and reduces the suppressive capacity of monocytic MDSCs in an intracranial mouse melanoma model. Oncoimmunology. 2015;4(4):e998107.

  [3] Van der Veken B, De Meyer GRY, Martinet W. Axitinib attenuates intraplaque angiogenesis, haemorrhages and plaque destabilization in mice. Vascul Pharmacol. 2018.