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. HSP990 is a potent HSP90 inhibitor with IC50 value of 0.6nM and 0.8nM for Hsp90α and Hsp90β (AlphaScreen competition binding assays), respectively, as well as shows inhibition against GRP94, an HSP90-like protein with IC50 value of 8.5nM. Treatment with HSP990 at concentration of 250nM over 30min could dissociate the complex of HSP90-p23, thus leading to the downregulation of the client protein c-Met and induction of HSP70, the biomarker for HSP90 inhibition, in c-Met amplified GTL-16 gastric tumor cells. In a study of a panel of cell lines and primary patient samples from a variety of tumor types, HSP990 showed anti-proliferation against most of the cells evaluated irrespective of cancer types or genetics, with GI50 values ranging in 4–40nM. In vivo study showed that HSP990 exhibited drug-like pharmaceutical and pharmacologic properties with high oral bioavailability, shown as sustained downregulation of c-Met and upregulation of Hsp70 induced by a single oral administration of 15 mg/kg HSP990. Oral administration of led to significant tumor growth inhibition in the BT-474 breast cancer model at dose of 5mg/kg or 10mg/kg HSP990 per week for 3 weeks, and in the MV4;11 AML model at dose of 5mg/kg twice a week or 10mg/kg once a week for 18 days^[1].
• 作用机制NVP-HSP990 binds to the N-terminal ATP-binding domain of Hsp90.^[1]

• 动物研究
  剂量	Mice[1]: 10 mg/kg, 15 mg/kg(p.o.); 5 mg/kg (i.v.)
  给药途径	p.o., i.v.
  动物药代数据	Animal Mice[1] Dose 5 mg/kg Administration i.v. AUC0→last 4333 ng·h/ml T1/2 2.5 h CL 19 ml/min/kg Cmax 6648 ng/ml Vss 2 L/kg