生物活性

• 描述The protein product of the MET proto-oncogene, c-Met, a receptor tyrosine kinase (RTK), is a prototype for the c-Met RTK subfamily and is activated by the ligand hepatocyte growth factor (HGF; scatter factor). Activation of the HGF/c‐Met pathway causes tumor progression, invasion, and metastasis^[3]. Moreover, the c-Met signaling pathway engages with other pathways, including that of the EGFR/human EGFR/MAPK/ERK pathway and can also promote angiogenesis through interaction with the VEGF and VEGF receptor (VEGFR) pathway. In addition, c-Met signaling can downregulate the antiangiogenic thrombospondin-1 and upregulate VEGF and upregulation of HGF and c-Met occurs after VEGF inhibition. Golvatinib (E7050, Eisai) is a highly potent, small-molecule, ATP-competitive inhibitor of c-Met and multiple members of the Eph receptor family, as well as c-Kit and Ron, with an IC₅₀ for c-Met of 0.001 μM^[4]. E7050 inhibits both c-Met and vascular endothelial growth factor receptor (VEGFR)-2 and inhibits phosphorylation of both c-Met and VEGFR-2. E7050 also potently represses the growth of both c-Met amplified tumor cells and endothelial cells stimulated with either HGF or VEGF. In a vitro study, MKN45 (gastric), SNU-5 (gastric), Hs746T (gastric), EBC-1 (lung), MKN74 (gastric), SNU-1 (gastric), A549 (lung) cell lines were treated with c-Met nonselective inhibitor E7050 at a dose ranging in 50-200 mg/kg to induce tumor regression and disappearance, indicating that E7050 is an efficient inhibitor of c-Met by inhibited phosphorylation of c-Met in tumors. In a vivo study, After different tumor cells were implanted subcutaneously (s.c.) into the mice respectively, E7050 was administered orally once a day at dose ranging from 25 mg/kg to 200 mg/kg for 8 to 15 days, suggesting that E7050 showed inhibition of the phosphorylation of c-Met in tumors, and strong inhibition of tumor growth and tumor angiogenesis. In a peritoneal dissemination model, MKN45 cells were inoculated intraperitoneally into nude mice and treated with E7050 at dose ranging from 25 mg/kg to 100 mg/kg for 6 days. E7050 showed an antitumor effect against peritoneal tumors as well as a significant prolongation of lifespan in treated mice. The results indicate that E7050 is a potent inhibitor of c-Met and VEGFR-2 and has therapeutic potential for the treatment of cancer^[3].
• 作用机制Golvatinib binds to the MET enzyme with a 2-aminopyridine hinge binder.
• 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
  NCT01355302	Advanced or Metastatic Solid T... more >>umors Previously Untreated Gastric Cancer Collapse <<	Phase 1 Phase 2	Terminated(Sites not recruitin... more >>g) Collapse <<	-	United States, Arizona ... more >> Arizona Oncology Associates, PC - CASA Tucson, Arizona, United States, 85715 United States, Florida Boca Raton Clinical Research Associates, Inc Plantation, Florida, United States, 33324 United States, Illinois Robert H. Lurie Comprenhensive Cancer Center of Northwestern University Chicago, Illinois, United States, 60611 United States, Michigan University of Michigan Comprehensive Cancer Center Ann Arbor, Michigan, United States, 48109 Barbara Ann Karmanos Cancer Institute Detroit, Michigan, United States, 48084 Henry Ford Medical Center Detroit, Michigan, United States, 48202 United States, North Carolina University of North Carolina at Chapel Hill Chapell Hill, North Carolina, United States, 27599 Duke University Medical Center Durham, North Carolina, United States, 27710 United States, Ohio Mercy Cancer Centerr at St. Anne Toledo, Ohio, United States, 43623 Russian Federation Chelyabinsk Regional Oncology Dispensary Chelyabinsk, Russian Federation, 454087 GOU VPO St-Petersburg SMA n/a Mechnikov Fed. Agen. of Healthcare and Social Developm. St Petersburg, Russian Federation, 195067 FSI "SRC of Oncology n. a. N.N.Petrov of Rosmedtekhnologiy" St Petersburg, Russian Federation, 197758 Ukraine SI Dnipropetrovsk Medical Academy of MOHU ch of Oncology and Medical Radiology Dnipropetrovsk, Ukraine, 49102 Municipal Clinical Medical and Prophylactic Institution Donetsk Regional Antitumor Centre Donetsk, Ukraine, 83092 Kyiv City Clinical Oncological Center Kyiv, Ukraine, 3115 Lviv State Oncol. Reg. Treatment and Diagnostic Center Lviv, Ukraine, 79031 United Kingdom Barts and the London NHS Trust London, Greater London, United Kingdom, EC1A 7BE Sarah Cannon Research UK London, Greater London, United Kingdom, W1G 6AD The Christie NHS Foundation Trust Manchester, Greater Manchester, United Kingdom, M20 4BX Collapse <<
  NCT01355302	-	-	Terminated(Sites not recruitin... more >>g) Collapse <<	-	-

• 参考文献

• [1] Wang W, Li Q, et al. Met kinase inhibitor E7050 reverses three different mechanisms of hepatocyte growth factor-induced tyrosine kinase inhibitor resistance in EGFR mutant lung cancer. Clin Cancer Res. 2012 Mar 15;18(6):1663-71.

  [2] Nakagawa T, Tohyama O, et al. E7050: a dual c-Met and VEGFR-2 tyrosine kinase inhibitor promotes tumor regression and prolongs survival in mouse xenograft models. Cancer Sci. 2010 Jan;101(1):210-5.

  [3] Nakagawa T, Tohyama O, Yamaguchi A, Matsushima T, Takahashi K, Funasaka S, Shirotori S, Asada M, Obaishi H. E7050: a dual c-Met and VEGFR-2 tyrosine kinase inhibitor promotes tumor regression and prolongs survival in mouse xenograft models. Cancer Sci. 2010 Jan;101(1):210-5. doi: 10.1111/j.1349-7006.2009.01343.x. Epub 2009 Sep 2. PMID: 19832844.

  [4] Molife LR, Dean EJ, Blanco-Codesido M, Krebs MG, Brunetto AT, Greystoke AP, Daniele G, Lee L, Kuznetsov G, Myint KT, Wood K, de Las Heras B, Ranson MR. A phase I, dose-escalation study of the multitargeted receptor tyrosine kinase inhibitor, golvatinib, in patients with advanced solid tumors. Clin Cancer Res. 2014 Dec 15;20(24):6284-94. doi: 10.1158/1078-0432.CCR-14-0409. Epub 2014 Oct 2. PMID: 25278451.