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]
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  human A2058 cells	-	Cytotoxicity assay	-	Cytotoxicity against human A2058 cells in presence of HSF1 knock down treatment, IC50=0.0052 μM	26164188
  human A375 cells	-	Cytotoxicity assay	-	Cytotoxicity against human A375 cells in presence of HSF1 knock down treatment, IC50=0.006 μM	26164188
  human GTL16 cells	-	Cytotoxicity assay	72 h	Cytotoxicity against human GTL16 cells after 72 hrs by CellTitre-Glo assay, IC50=0.014 μM	25368984

• 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

• 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
  NCT00879905	Advanced Solid Malignancies	Phase 1	Completed	-	Canada, Ontario ... more >> Novartis Investigative Site Toronto, Ontario, Canada, M5G 2M9 France Novartis Investigative Site Toulouse Cedex 3, France, 31052 Spain Novartis Investigative Site Barcelona, Cataluña, Spain, 08035 Collapse <<
  NCT01064089	Advanced Solid Tumors	Phase 1	Terminated	-	Japan ... more >> Novartis Investigative Site Nagoya, Aichi, Japan, 466-8560 Novartis Investigative Site Kashiwa, Chiba, Japan, 277-8577 Collapse <<

• 参考文献

• [1] Menezes DL, Taverna P, et al. The novel oral Hsp90 inhibitor NVP-HSP990 exhibits potent and broad-spectrum antitumor activities in vitro and in vivo. Mol Cancer Ther. 2012 Mar;11(3):730-9.