生物活性

• 靶点

  IGF-1R IC50:1.8nM

  Insulin Receptor IC50:1.7nM

• 描述IGF-1R (insulin-like growth factor-1 receptor) plays a key role in transformation, growth and survival of malignant cells, and has been considered as a general and promising target for cancer treatment. BMS-754807 is a multi-target tyrosine kinase inhibitor, most potent to IGF-1R and IR with IC50 values of 1.8nM and 1.7nM, as well as showed less potency to Met, RON, TrkA, TrkB, AurA, and AurB with IC50 values of 6, 44, 7, 4, 9, and 25nM, respectively^[1]. BMS-754807 could inhibit the phosphorylation of IGF-1R and the downstream AKT and MAPK (ERK) with IC50 values of 13nM, 22nM and 13nM, as well as showed anti-proliferation with IC50 of 7nM in IGF-Sal cell line^[2]. BMS-754807 at concentration of 50nM for >4h induced apoptosis, shown by cleaved PARP and Caspase 3 as well as sub-G1 arrest, in Rh41 cells. BMS-754807 exhibited inhibition on cell growth of a broad range of tumor cell lines of various histologic origins including Ewing's, rhabdomyosarcoma, neuroblastoma, liposarcoma, breast, lung, pancreatic, colon, gastric, multiple myeloma and leukemia, with IC50 ranging in 5-365nM in most cell lines. Consistent with this, BMS-754807 showed in vivo antitumor activity in various preclinical tumor models in mice and efficient to a selected group of epithelial (IGF-1R-Sal, GEO, and Colo205), hematopoietic (JJN3), and mesenchymal (RD1 and Rh41) xenograft tumor models with tumor growth inhibition ranging in 53% to 115% after oral administration of BMS-754807 at dose ranging in 3.1-50mg/kg. As BMS-754807 inhibited both IGF-1R and IR, an oral glucose tolerance test showed that increased serum glucose level to 1.1-1.6 fold within 1h posttreatment could be observed in rodents dosed of 3.125 and 12.5mg/kg BMS-754807 at 30min before glucose challenge, with remained elevated insulin level by 2h posttreatment^[1].
• 作用机制BMS-754807 is a reversible ATP-competitive antagonist of IGF-1R and inhibits the catalytic domain of the IGF-1R.^[2]
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  1483	~5 μM	Growth inhibitory assay	-	IC50=2.19 μM	19996272
  151-B	~5 μM	Growth inhibitory assay	-	IC50=2.67 μM	19996272
  22-r-1	~5 μM	Growth inhibitory assay	-	IC50=0.175 μM	19996272

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• 动物研究
  剂量	Nude Mice: 3.125mg/kg - 25 mg/kg[1] (p.o.)
  给药途径	p.o.
  动物药代数据	Animal Nude mice[1] Dose 6.25 mg/kg Administration p.o. Cmax 71 nmol/L Tmax 0.5 h

• 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
  NCT00793897	Advanced Solid Tumors ... more >> Metastatic Solid Tumors Collapse <<	Phase 1	Completed	-	Australia, Victoria ... more >> Local Institution East Melbourne, Victoria, Australia, 3002 Local Institution Parville, Victoria, Australia, 3050 Canada, Alberta Local Institution Edmonton, Alberta, Canada, T6G 1Z2 Canada, Ontario Local Institution Hamilton, Ontario, Canada, L8V 5C2 Korea, Republic of Local Institution Seoul, Korea, Republic of, 138-736 Collapse <<
  NCT01225172	Breast Cancer	Phase 2	Completed	-	United States, Alabama ... more >> Univ Of Al At Birmingham Birmingham, Alabama, United States, 35294 United States, Arizona Mayo Clinic Arizona Scottsdale, Arizona, United States, 85259 United States, California Sharp Clinical Oncology Research San Diego, California, United States, 92123 United States, Florida Mayo Clinic Jacksonville, Florida, United States, 32224 United States, Illinois University Of Chicago Medical Center Chicago, Illinois, United States, 60637 Illinois Cancercare, Pc Peoria, Illinois, United States, 61615 United States, Indiana Indiana University Health Goshen Center For Cancer Care Goshen, Indiana, United States, 46526 United States, Maryland Sidney Kimmel Comprehensive Cancer Center At Johns Hopkins Baltimore, Maryland, United States, 21231 Oncology Care Associates, P.A. Wheaton, Maryland, United States, 20902 United States, Minnesota Masonic Cancer Ctr, University Of Minnesota Minneapolis, Minnesota, United States, 55455 Mayo Clinic Rochester, Minnesota, United States, 55905 United States, North Carolina Unv. Of Nc At Chapel Hill Chapel Hill, North Carolina, United States, 27599 Presbyterian Hospital Cancer Research Charlotte, North Carolina, United States, 28204 Duke University Medical Center-Dept Of Medicine Durham, North Carolina, United States, 27710 United States, Texas Ut Md Anderson Can Ctr. Houston, Texas, United States, 77030 United States, Virginia University Of Virginia Health System Charlottesville, Virginia, United States, 22908 United States, Wisconsin University Of Wisconsin Madison, Wisconsin, United States, 53792 Collapse <<
  NCT00788333	Breast Cancer	Phase 1 Phase 2	Completed	-	Australia, South Australia ... more >> Local Institution Kurralta Park, South Australia, Australia, 5037 Australia, Victoria Local Institution Frankston, Victoria, Australia, 3199 Local Institution Geelong, Victoria, Australia, 3220 Belgium Local Institution Brussels, Belgium, 1000 Canada, Ontario Local Institution Ottawa, Ontario, Canada, K1H 8L6 Local Institution Toronto, Ontario, Canada, M5G 1X5 Hungary Local Institution Budapest, Hungary, 1122 Local Institution Miskolc, Hungary, 3526 United Kingdom Local Institution Newcastle Upon Tyne, Tyne And Wear, United Kingdom, NE7 7DN Collapse <<

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