生物活性

• 描述Human XPO1 (exportin-1) is the key nuclear-cytoplasmic transport protein which can export many cargo proteins out of the nucleus. Inhibition of XPO1 resulting in nuclear accumulation of these proteins causes cancer cell death. KPT-8602 is a second-generation XPO1 inhibitor with potency against a panel of leukemia cell lines. Compared with the previous selective inhibitor of nuclear export (SINE) compound KPT-330, KPT-8602 demonstrates substantially reduced brain penetration thus resulting its attenuation of the central nervous system mediated side effects of anorexia and weight loss. KPT-8602 inhibited the XPO1 dependent nuclear export with an EC50 value of 60.9nM in HeLa cells stably expressing this GFP reporter protein. Treatment with KPT-8602 at concentration of 0.3 and 1μM overnight caused significantly decreased levels of XPO1 protein by proteolytic degradation mechanism. KPT-8602 induced cytotoxicity with EC50 values ranging in 25-145nM in a panel of leukemia cell lines post 72-hour treatment and induced apoptosis of Jurkat and MOLT-4 T-ALL shown as cleaved PARP as early as 6 hours after treatment at concentration of 1μM. As an important cargo of XPO1, an increased p53 nuclear and upregulation and stabilization of p53 shown by phosphorylated (Ser15) could be observed in MOLT-4 post KPT-8602 treatment. Oral administration of KPT-8602 at dose of 5mg/kg or 15mg/kg, daily, for 19 days, showed potent anti-lymphoblastic leukemia activity in MOLT-4 subcutaneous xenografted mice. Also it prolonged survival of patient derived xenograft models of ALL. A tumor cell-specific 3D nuclear telomere organization is sensitive to XPO1 inhibition by KPT-8602.

• 动物研究
  剂量	Mice: 15 mg/kg[1] (p.o.)
  给药途径	p.o.