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]
Onalespib 细胞研究
细胞系
浓度
检测类型
检测时间
活性说明
数据源
human A231 cells
Proliferation assay
48 h
Antiproliferative activity against human A231 cells after 48 hrs by MTT assay, IC50=1.01 μM
24763261
human HCT116 cells
Cytotoxic assay
Cytotoxicity against human HCT116 cells by Alamar blue assay, IC50=0.048 μM
20662534
human HCT116 cells
Proliferation assay
48 h
Antiproliferative activity against human HCT116 cells after 48 hrs by MTT assay, IC50=0.08 μM
24763261
human HCT116 cells
10 nM
Function assay
18 h
Induction of apoptosis in human HCT116 cells assessed as upregulation of Hsp70 level at 10 nM after 18 hrs by immunoblotting
搜索
