生物活性

• 靶点

  Amyloid-β 40 EC50:14nM

  Notch EC50:5nM

  γ secretase IC50:4nM

• 描述RO4929097 is a potent and selective γ-secretase inhibitor with IC50 value of 4nM for γ-secretase enzyme assay, as well as EC50 values of 14nM and 5nM for Aβ40 and Notch processing in engineered cell lines, respectively. As γ-secretase is the key component of the enzymatic complex cleaving and activating NOTCH, RO4929097 can also inhibit NOTCH signaling indirectly. Treatment with RO4929097 dose-dependently suppressed the production of intracellular Notch at concentration ranging in 0.1-5μM for 5 days, reduced the expression of the downstream Notch target Hes1 at concentration ranging in 0.1-1μM for 24h, and producd a less transformed morphology in A549 cells. Orally administration of RO4929097 at dose of 3, 10, 30 and 60mg/kg, qd, for 14 days achieved tumor growth inhibition by 66%, 77%, 79% and 88% in the A549 xenograft model. Treatment with 60 mg/kg RO4929097 twice daily with the 7+/14- schedule for a 21-day cycle achieved tumor growth inhibition by 91%. Inhibition of tumor growth remained prolonged and sustained up to 34 days post-treatment with reduced expression of several key angiogenic genes tested.
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  MGG23	30 μM	Cell Viability Assay	4 d	decreases cell viability	24495907
  MGG4	30 μM	Cell Viability Assay	4 d	decreases cell viability	24495907
  MGG6	30 μM	Cell Viability Assay	4 d	decreases cell viability	24495907

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• 动物研究
  剂量	Mice: 10 mg/kg[2] (p.o.) Nude Mice: 3 mg/kg - 60 mg/kg[1] (p.o.)
  给药途径	p.o.
  动物药代数据	Animal Nude mice[1] Dose 10 mg/kg Administration p.o. AUC24 h 1100 ng·h/ml

• 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
  NCT00532090	Neoplasms	Phase 1	Completed	-	United States, Colorado ... more >> Aurora, Colorado, United States, 80045 United States, Massachusetts Boston, Massachusetts, United States, 02114 Boston, Massachusetts, United States, 02115 Boston, Massachusetts, United States, 02215 United States, New Jersey New Brunswick, New Jersey, United States, 08901 United States, Texas Houston, Texas, United States, 77030 San Antonio, Texas, United States, 98229 Collapse <<
  NCT01218620	Adult Solid Neoplasm	Phase 1	Completed	-	United States, Wisconsin ... more >> University of Wisconsin Hospital and Clinics Madison, Wisconsin, United States, 53792 Collapse <<
  NCT01236586	Lymphoma Brai... more >>n Neoplasms Sarcoma Osteosarcoma Wilm's Tumor Collapse <<	Phase 1	Withdrawn	-	United States, Maryland ... more >> National Institutes of Health Clinical Center, 9000 Rockville Pike Bethesda, Maryland, United States, 20892 United States, Tennessee St. Jude Childrens Research Hospital Memphis, Tennessee, United States, 38105 Collapse <<

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• 参考文献

• [1] Luistro L, He W, et al. Preclinical profile of a potent gamma-secretase inhibitor targeting notch signaling with in vivo efficacy and pharmacodynamic properties. Cancer Res. 2009 Oct 1;69(19):7672-80.

  [2] Huynh C, Poliseno L, et al. The novel gamma secretase inhibitor RO4929097 reduces the tumor initiating potential of melanoma. PLoS One. 2011;6(9):e25264.