生物活性

• 靶点	Notch IC50:0.41nM

• 描述LY3039478 is a potent Notch-1 intracellular domain (N1ICD) cleavage inhibitor with IC50 value of 0.41nM in SAR assays^[1]. It inhibited N1ICD cleavage and expression of Notch-regulated genes in the tumor microenvironment, and also resulted in the induction of apoptosis in a Notch-dependent xenograft model^[2]. LY3039478 at concentration of 1μM and 10μM significantly inhibited the growth of Caki and 769-P, with decreased expression of Myc and Cyclin A1, two protein driven by Notch. G0/G1 cell cycle arrest could also be observed. Oral administration of LY3039478, 3 days per week, led a significant increase of survival and delayed tumor growth of immunodeficient NSG mice xenografted with 769-P CCRCC cells^[3].
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  A2780 cells	-	Function assay	24 h	Inhibition of gamma-secretase mediated cleavage of Notch 1 in human A2780 cells assessed as nuclear accumulation of Notch 1 intracellular domain (N1ICD) after 24 hrs by ELISA, IC50=0.00103 μM	24900678
  A375 cells	-	Function assay	24 h	Inhibition of gamma-secretase mediated cleavage of Notch 1 in human A375 cells assessed as nuclear accumulation of Notch 1 intracellular domain (N1ICD) after 24 hrs by ELISA, IC50=0.00048 μM	24900678
  BxPC3 cells	-	Function assay	24 h	Inhibition of gamma-secretase mediated cleavage of Notch 1 in human BxPC3 cells assessed as nuclear accumulation of Notch 1 intracellular domain (N1ICD) after 24 hrs by ELISA, IC50=0.00039 μM	24900678

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• 动物研究
  剂量	Mice: 8 mg/kg[3] (p.o.)
  给药途径	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
  NCT01695005	Neoplasms Neo... more >>plasm Metastasis Lymphoma Collapse <<	Phase 1	Completed	-	United States, Florida ... more >> University of Miami School of Medicine Miami, Florida, United States, 33136 United States, Massachusetts Harvard Medical School Boston, Massachusetts, United States, 02215 United States, Michigan University of Michigan Ann Arbor, Michigan, United States, 48109 United States, New York Montefiore Medical Center Bronx, New York, United States, 10461 Columbia University Medical Center New York, New York, United States, 10032 Denmark For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Kobenhavn, Denmark, 2100 France For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Paris, France, 75248 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Villejuif, France, 94805 Germany For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Tübingen, Germany, 72076 Spain For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Barcelona, Spain, 08035 United Kingdom For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. London, United Kingdom, SE1 9RT Collapse <<
  NCT03502577	Recurrent Plasma Cell Myeloma ... more >> Refractory Plasma Cell Myeloma Collapse <<	Phase 1	Recruiting	July 30, 2034	United States, Washington ... more >> Fred Hutch/University of Washington Cancer Consortium Recruiting Seattle, Washington, United States, 98109 Contact: Immunotherapy Trials Intake, SCCA    206-606-4668    immunotherapy@seattlecca.org    Principal Investigator: Andrew J. Cowan Collapse <<
  NCT02784795	Solid Tumor B... more >>reast Cancer Colon Cancer Cholangiocarcinoma Soft Tissue Sarcoma Collapse <<	Phase 1	Active, not recruiting	January 31, 2019	United States, Florida ... more >> Sylvester Comprehensive Cancer Center Miami, Florida, United States, 33136 United States, Michigan Karmanos Cancer Institute Detroit, Michigan, United States, 48201 United States, New York Memorial Sloan Kettering Cancer Center New York, New York, United States, 10065 United States, Texas University of Texas MD Anderson Cancer Center Houston, Texas, United States, 77030 Denmark Rigshospitalet Copenhagen, København Ø, Denmark, 2100 France Institut Bergonie Bordeaux, France, 33076 Centre Leon Berard Lyon Cedex 08, France, 69373 Gustave Roussy Villejuif Cedex, France, 94805 Spain Hospital Universitari Vall d'Hebron Barcelona, Spain, 08035 Fundacion Jimenez Diaz Madrid, Spain, 28040 Hospital Madrid Norte Sanchinarro Madrid, Spain, 28050 Collapse <<

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• 参考文献

• [1] Warren J. P. Discovery of a Novel Notch Inhibitor.The 8th SCI-RSC Symposium on Proteinase Inhibitor Design April 15-16, 2013, Basel, Switzerland.

  [2] Mark H. B, Hong G, et al. Novel inhibitor of Notch signaling for the treatment of cancer. Abstract 1131, AACR 104th Annual Meeting 2013.

  [3] Bhagat TD, Zou Y, et al. Notch Pathway Is Activated via Genetic and Epigenetic Alterations and Is a Therapeutic Target in Clear Cell Renal Cancer. J Biol Chem. 2017 Jan 20;292(3):837-846.