生物活性

• 描述HSP90 (heat shock protein 90) is a cellular ubiquitous molecular chaperone responsible for promoting the conformational mutation and stabilization of several client oncoproteins, including Met, B-Raf, p53, Akt, and Kit, function of which is required by tumor cells to maintain appropriate client protein expression necessary for proliferation and survival. BIIB021 is a synthetic inhibitor of HSP90 with Ki value of 1.7nM (measured by Hsp90 binding assay). All the protein level the client protein tested, including HER-2, IGF-I receptor, AKT, Raf-1, Cdk4, Cdk6 and progesterone receptor, was decreased and the protein level of Hsp90α and Hsp70 was increased due to the inhibition of HSP90 by BIIB021 at concentration>100nM for 24h in MCF-7 cells. And this effect on the client protein can also be observed in the BT474 breast tumor xenograft model at 6h post dose of 30-120mg/kg BIIB021. The antiproliferation activity of BIIB021 can be observed in various cell lines, including BT474, MCF-7, N87, HT29, H1650, H1299, H69 and H82, with IC50 values ranging in 0.06-0.31μM. The antitumor effect of oral administration of BIIB021, five days per week for 4 weeks or 5 weeks, can be observed in several models, as tumor growth inhibition can be achieved by 87% at dose of 125mg/kg in N87 xenografts, 94% at dose of 120mg/kg in BT474 xenografts, 85% at dose of 120mg/kg in CWR22 xenografts, 70% at dose of 75mg/kg (BID) in U87 xenografts, 67% at dose of 124mg/kg in SKOV3 cells and 51% at dose of 124mg/kg in Panc-1 xenografts^[1].
• 作用机制BIIB021 exhibits competitive binding with geldanamycin and binds the ATP pocket of Hsp90.^[1]
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  human BT474 cells	-	Function assay	-	Binding affinity to Hsp90 nucleotide binding domain in human BT474 cells, IC50=0.14 μM	20608738
  MCF7 cells	-	Function assay	-	Inhibition of HSP90alpha in human MCF7 cells assessed as degradation of Her-2, EC50=38 nM	22938030
  NCI-H1299 cells	-	Function assay	12 h	Reduction in oxygen consumption rate in human NCI-H1299 cells incubated for 12 hrs	25383915

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• 动物研究
  剂量	Nude Mice[1] (p.o.): 30 mg/kg - 150 mg/kg
  给药途径	p.o.
  动物药代数据	Animal Mice[1] Dose 75 mg/kg Administration p.o. AUC0→last 2.3 μg·h/ml T1/2 0.5 h Tmax 5 min Cmax 10.2 μg/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
  NCT00412412	Breast Cancer	Phase 1	Completed	-	United States, Florida ... more >> Research Site Tampa, Florida, United States, 33612 United States, New York Research Site New York, New York, United States, 10021 United States, Texas Research site Houston, Texas, United States, 77030 Collapse <<
  NCT00345189	Tumors Lympho... more >>ma Collapse <<	Phase 1	Completed	-	United States, Arizona ... more >> Research site Scottsdale, Arizona, United States, 85258 United States, Connecticut Research site New Haven, Connecticut, United States, 06520 United States, Texas Research site San Antonio, Texas, United States, 78245 United Kingdom Research site Sutton, Surrey, United Kingdom, SM2 5PT Collapse <<
  NCT00344786	B-Cell Chronic Lymphocytic Leu... more >>kemia Collapse <<	Phase 1	Terminated(Sponsor's decision)	-	United States, California ... more >> Research Site San Diego, California, United States, 92093 United States, New York Research site New York, New York, United States, 10021 United States, Texas Research site Houston, Texas, United States, 77030 Collapse <<

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