生物活性

• 靶点	HSP90 IC50:18nM

• 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. Onalespib is a potent HSP90 inhibitor with Kd value of 0.71nM. Treatment with Onalespib led to the down-regulation of the oncogenic client proteins Raf-1 and CDK4 at concentration around 30nM, as well as growth inhibition with IC50 value of 48nM in HCT116 cells. The up-regulation of Hsp70 can be observed at concentration>10nM, which was regarded as a biomarker readout for Hsp90 inhibition. Intraperitoneal injection with the L-lactate salt form of Onalespib at dose of 60mg/kg per day for 3 days on and 3 days off for four cycles caused tumor growth inhibition by 78% in HCT116nhuman colon cancer xenografts and a tumor growth delay of 17 days after cessation of dosing^[1].
• 作用机制Onalespib can bind in the ATPase binding site of HSP90.^[1]

• 动物研究
  剂量	Mice: 55 mg/kg weekly[2] (i.p.), 80 mg/kg[3] (i.p.), 30 mg/kg[4] (i.v.)
  给药途径	i.p., i.v.
  动物药代数据	Animal Mice[1] Administration i.v. CL 113 - 200 ml/min/kg T1/2 0.9 - 3.2 h Vd 11 - 13 L/kg