生物活性

• 靶点	HSP90 IC50:0.92μM

• 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. SNX-2112 and its prodrug SNX-5422 are HSP90 inhibitors with IC50 value of 30nM (measured by ATP displacement assay). Treatment with SNX-2112 led to downregulation of protein level of HER2 and AKT signaling, in a time-dependent (at 1μM with 48h) and dose-dependent (<1μM for 24h) in BT-474 cells. SNX-2112 inhibited cell proliferation of a panel of breast, lung, and ovarian cancer cell lines with IC50 values ranging in 10-50nM, and also caused a profound mitotic block in MDA-468 cells at 1μM for 48h. Consistent with apoptosis induced by SNX-2112, increased cleaved PARP and decreased CDK1 can also be observed in BT-474 cells treated with SNX-2112. A single dose of 50m/kg SNX-2112 can repeat the effect on the client protein in vivo, with most potency at 10h post dose. Oral administration of SNX-2112 at dose of 50mg/kg, 5 days per week, could significantly inhibit tumor growth in BT474 tumor xenografts after treatment for 4 weeks, and in H1650 tumor xenografts after treatment for 37 days^[1].
• 作用机制SNX-2112 binds to the amino-terminal ATP site of Hsp90.^[1]

• 动物研究
  剂量	Mice[1] (p.o.): 10 mg/kg - 200 mg/kg
  给药途径	p.o.
  动物药代数据	Animal Rats[2] Dose 2 mg/kg Administration i.v. AUC0-inf 4.79 μM·h k21 0.325 l/h k12 0.85 l/h MRT 8.98 h MRT0→t 4.02 μM·h C0 1.93 μM Vss 2.02 L T1/2β 7.89 h CL 0.225 l/h T1/2α 0.465 h k10 0.403 l/h