生物活性

• 靶点	c-Met Ki:2nM

• 描述The human MET proto-oncogene encodes the MET kinase, also known as HGF receptor. The HGF/MET signaling pathway regulates a wide variety of normal cellular functions that can be subverted to support neoplasia including cell proliferation, survival, apoptosis, scattering and motility, invasion, and angiogenesis. LY2801653 is designed as a potent, orally bioavailable c-Met inhibitor. The mean IC_{50 value of LY2801653 for inhibition of MET auto-phosphorylation in HGF-stimulated H460 cells was 35.2 ± 6.9 nM and the IC50 for MET auto-phosphorylation in S114 cells was 59.2 nM. LY2801653, in the concentration range of 0.01–10 μM, completely blocked the HGF-induced DU-145 cell scattering. LY2801653 also demonstrated potent anti-proliferative activity in cell lines with MET gene amplification (MKN45, Hs746T and H1993). MET target inhibition studies to assess activity of LY2801653 were undertaken in S114 xenograft tumors created through subcutaneous implantation of S114 cells, a murine cell line engineered to express both human MET and HGF. MET phosphorylation was inhibited by 98 % with a single dose of 50-mg/kg LY2801653 for 2 h. Furthermore, LY2801653 treatment inhibited MET phosphorylation with a composite TED50 (50 % target inhibition dose) of 1.2 mg/kg and a composite TED90 of 7.4 mg/kg ^[3].}
• 作用机制LY2801653 bound MET is in an inactive form with the activation loop DFG motif adopting a DFG-out conformation .
• 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
  NCT02791334	Solid Tumor M... more >>icrosatellite Instability-High (MSI-H) Solid Tumors Cutaneous Melanoma Pancreatic Cancer Breast Cancer (HR+HER2-) Collapse <<	Phase 1	Recruiting	July 31, 2020	United States, Tennessee ... more >> Sarah Cannon Research Institute SCRI Recruiting Nashville, Tennessee, United States, 37203 Contact    615-329-7274       Principal Investigator: SMO Sarah Cannon Research Inst.          Tennessee Oncology PLLC Recruiting Nashville, Tennessee, United States, 37203 Contact    6153297274       Principal Investigator: Johanna Chock Bendell          United States, Texas University of Texas MD Anderson Cancer Center Recruiting Houston, Texas, United States, 77030 Contact    713-745-6754       Principal Investigator: Timothy Yap          The START Center for Cancer Care Recruiting San Antonio, Texas, United States, 78229 Contact    210-593-5270       Principal Investigator: Amita Patnaik          Belgium Cliniques Universitaires Saint-Luc Recruiting Brussels, Belgium, 1200 Contact    327645106       Principal Investigator: Jean-Pascal Machiels          Universitair Ziekenhuis Antwerpen Recruiting Edegem, Belgium, 2650 Contact    3238213954       Principal Investigator: Marc Peeters          Canada, Ontario Princess Margaret Hospital Recruiting Toronto, Ontario, Canada, M5TY 2M9 Contact    4169464501       Principal Investigator: Marcus O Butler          France Institut Bergonie Recruiting Bordeaux, France, 33076 Contact    33556333253       Principal Investigator: Antoine Italiano          Gustave Roussy Recruiting Villejuif Cedex, France, 94805 Contact    33142114385       Principal Investigator: Antoine Hollebecque          Korea, Republic of Seoul National University Hospital Recruiting Seoul, Korea, Republic of, 03080 Contact    82220722390       Principal Investigator: YUNG-JUE BANG          Severance Hospital Yonsei University Health System Recruiting Seoul, Korea, Republic of, 03722 Contact    82222288132       Principal Investigator: Hyun Cheol Chung          Spain Fundacion Jimenez Diaz Not yet recruiting Madrid, Spain, 28040 Contact    34915504800       Principal Investigator: Victor Moreno          Hospital Madrid Norte Sanchinarro Recruiting Madrid, Spain, 28050 Contact    34917567825       Principal Investigator: Maria Jose Miguel Luken          Taiwan National Cheng Kung University Hospital Recruiting Tainan, Taiwan, 704 Contact    88662353535       Principal Investigator: Wu-Chou Su          National Taiwan University Hospital Recruiting Taipei, Taiwan, 10048 Contact    +886223123456 ext. 67680       Principal Investigator: Chia-Chi Lin Collapse <<
  NCT02920996	Carcinoma, Non-Small-Cell Lung... more >> Solid Tumor Collapse <<	Phase 2	Recruiting	March 2024	United States, Massachusetts ... more >> Massachusetts General Hospital Recruiting Boston, Massachusetts, United States, 02114 Contact: Rebecca Heist, MD    617-724-4000    RHeist@partners.org    Principal Investigator: Rebecca Heist, MD          Dana-Farber Cancer Institute Recruiting Boston, Massachusetts, United States, 02115 Contact: Mark Awad, MD    617-632-3468    Mark_awad@dfci.harvard.edu    Principal Investigator: Mark Awad, MD Collapse <<
  NCT03125239	Relapsed Adult Acute Myeloid L... more >>eukemia Refractory Adult Acute Myeloid Leukemia Collapse <<	Phase 1	Recruiting	June 1, 2020	United States, Massachusetts ... more >> Brigham and Women's Hospital Enrolling by invitation Boston, Massachusetts, United States, 02115 Dana-Farber Cancer Institute Recruiting Boston, Massachusetts, United States, 02215 Contact: Jacqueline S Garcia, MD    617-632-6349    jacqueline_garcia@dfci.harvard.edu    Principal Investigator: Jacqueline S Garcia, MD Collapse <<

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• 参考文献

• [1] Kosciuczuk EM, Saleiro D, et al. Merestinib blocks Mnk kinase activity in acute myeloid leukemia progenitors and exhibits antileukemic effects in vitro and in vivo. Blood. 2016 Jul 21;128(3):410-4.

  [2] Yan SB, Peek VL, et al. LY2801653 is an orally bioavailable multi-kinase inhibitor with potent activity against MET, MST1R, and other oncoproteins, and displays anti-tumor activities in mouse xenograft models. Invest New Drugs. 2013 Aug;31(4):833-44.

  [3] Yan SB, Peek VL, Ajamie R, Buchanan SG, Graff JR, Heidler SA, Hui YH, Huss KL, Konicek BW, Manro JR, Shih C, Stewart JA, Stewart TR, Stout SL, Uhlik MT, Um SL, Wang Y, Wu W, Yan L, Yang WJ, Zhong B, Walgren RA. LY2801653 is an orally bioavailable multi-kinase inhibitor with potent activity against MET, MST1R, and other oncoproteins, and displays anti-tumor activities in mouse xenograft models. Invest New Drugs. 2013 Aug;31(4):833-44. doi: 10.1007/s10637-012-9912-9. Epub 2012 Dec 29. PMID: 23275061; PMCID: PMC3717159.