生物活性

• 靶点	c-Met IC50:5nM

• 描述The MET receptor tyrosine kinase (RTK) plays a central role in regulating cell growth, survival, and invasion. Binding of hepatocyte growth factor (HGF) promotes MET dimerization, stimulating MET kinase activity. AMG 337 is an oral, small molecule, ATP-competitive, highly selective inhibitor of the MET receptor. It potently inhibits the enzymatic activity of WT MET (IC₅₀ = 1 nM) and a subset of MET mutants found in papillary renal cell carcinoma. AMG 337 also inhibits cell based HGF-induced MET phosphorylation in PC3 cells (IC₅₀ = 5 nM). Competitive binding assays illustrated the selectivity of AMG 337, binding only MET when profiled against a diverse panel of 402 human kinases. AMG 337 inhibits proliferation in MET-dependent cancer cell lines following 72 hours of treatment with AMG 337. MET phosphorylation was completely inhibited in the gastric cancer cells lines MKN-45, SNU-620, and SNU-5 cells, following a 2-hour treatment with 100 nM AMG 337. In MKN-45 cells, 300 nM AMG 337 treatment for 24 hours resulted in a dose-dependent increase in cells in the G₁ phase; with concurrent reduction of cells in S-phase. AMG 337 at a 0.5 mg/kg dose robustly inhibited Gab-1 (a kind of adaptor protein) phosphorylation, and escalation to 0.75 mg/kg or more resulted in >90% inhibition of MET signaling in the TPR-MET mouse tumor model ^[3].
• 作用机制AMG 337 binds to a well-defined, inactive conformation of the MET activation loop (A-loop) in a binding mode .
• 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
  NCT02096666	Stomach Neoplasms	Phase 1 Phase 2	Active, not recruiting	December 7, 2018	Japan ... more >> Research Site Kashiwa-shi, Chiba, Japan, 277-8577 Research Site Sapporo-shi, Hokkaido, Japan, 060-8648 Research Site Kawasaki-shi, Kanagawa, Japan, 216-8511 Research Site Suntou-gun, Shizuoka, Japan, 411-8777 Collapse <<
  NCT01253707	Advanced Malignancy ... more >> Advanced Solid Tumors Cancer Oncology Oncology Patients Tumors Collapse <<	Phase 1	Completed	-	United States, California ... more >> Research Site Los Angeles, California, United States, 90025 United States, Georgia Research Site Atlanta, Georgia, United States, 30332 United States, Illinois Research Site Chicago, Illinois, United States, 60637 United States, Massachusetts Research Site Boston, Massachusetts, United States, 02114 United States, Michigan Research Site Detroit, Michigan, United States, 48201 United States, Ohio Research Site Columbus, Ohio, United States, 43210 United States, Tennessee Research Site Nashville, Tennessee, United States, 37232 United States, Texas Research Site Houston, Texas, United States, 77030 Collapse <<
  NCT02344810	Adenocarcinoma of the Esophagu... more >>s Adenocarcinoma of the Gastroesophageal Junction Diffuse Adenocarcinoma of the Stomach Gastrointestinal Cancer Intestinal Adenocarcinoma of the Stomach Mixed Adenocarcinoma of the Stomach Stage IIIA Esophageal Cancer Stage IIIA Gastric Cancer Stage IIIB Esophageal Cancer Stage IIIB Gastric Cancer Stage IIIC Esophageal Cancer Stage IIIC Gastric Cancer Stage IV Esophageal Cancer Stage IV Gastric Cancer Collapse <<	Phase 1 Phase 2	Withdrawn(The study did not op... more >>en to accrual. No start date and no completion dates.) Collapse <<	March 6, 2020	United States, Pennsylvania ... more >> ECOG-ACRIN Cancer Research Group Philadelphia, Pennsylvania, United States, 19103 Collapse <<

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• 参考文献

• [1] Hughes PE, Rex K, et al. In Vitro and In Vivo Activity of AMG 337, a Potent and Selective MET Kinase Inhibitor, in MET-Dependent Cancer Models. Mol Cancer Ther. 2016 Jul;15(7):1568-79.

  [2] Cecchi F, Rabe DC, et al. Targeting the HGF/Met signaling pathway in cancer therapy. Expert Opin Ther Targets. 2012 Jun;16(6):553-72.

  [3] Hughes PE, Rex K, Caenepeel S, Yang Y, Zhang Y, Broome MA, Kha HT, Burgess TL, Amore B, Kaplan-Lefko PJ, Moriguchi J, Werner J, Damore MA, Baker D, Choquette DM, Harmange JC, Radinsky R, Kendall R, Dussault I, Coxon A. In Vitro and In Vivo Activity of AMG 337, a Potent and Selective MET Kinase Inhibitor, in MET-Dependent Cancer Models. Mol Cancer Ther. 2016 Jul;15(7):1568-79. doi: 10.1158/1535-7163.MCT-15-0871. Epub 2016 Apr 19. PMID: 27196782.