生物活性

• 靶点

  HSP70 IC50:0.5μM

  HSPA8 IC50:2.6μM

  GRP78 IC50:2.6μM

• 描述HSC70 and HSP70 are the two major cytosolic isoforms of the HSP70 family. Between this two proteins, HSP70 is present at relatively low levels in normal cells but can be elevated in expression to protect cells from apoptosis in response to various stressful stimuli such as anticancer agents, especially the HSP90 inhibitors, making it become an important target for anticancer therapy due to its antiapoptotic and oncogenic functions. VER-155008 is a potent inhibitor for Hsp70, Hsc70 and Grp78 with IC50 values of 0.5μM, 2.6 μM and 2.6μM (measured by fluorescence polarisation (FP) assay), respectively. In celluar study, exposure to VER-155008 at 40μM showed a similar response like treatment with HSP90 inhibitor 17-AAG in BT474 or HCT116 cells, like induction of the degradation of HSP90 client protein Her2 and Raf-1, except no induction of HSP70 protein observed. Apoptosis to different extent can be observed in BT474, MDA-MB-468, HCT116 or HT29 cells exposure to VER-155008 at concentration of 0.5μM or 20μM for 24h. Complete colony forming ability of HCT116 or HT29 cells following a 48h-exposure to VER-155008 at concentration>40μM. Combined treatment with VER-155008 at varying concentration to HSP90 inhibitors, 0.5μM VER-82160 or 0.5μM 17-AAG for 24h, could dose-dependently elevate the potency of this two HSP90 to induce cell apoptosis. These suggest that the best use of a small molecule Hsc70/Hsp70 inhibitor, VER-155008, will be in combination with an Hsp90 inhibitor^[1].
• 作用机制VER-155008 and bind in the ATPase pocket of Hsp70 and inhibit its intrinsic ATPase activity.^[1]

• 动物研究
  剂量	Mice[1] (i.v.): 25 mg/kg, 40 mg/kg
  给药途径	i.v.
  动物药代数据	Animal Mice[1] Dose 25 mg/kg Administration i.v. T1/2 0.6 h CL 49 ml/min/kg