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]

• 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