Xevinapant

XIAP BIR3:66.4 nM(Ki)|CIAP2-BIR3:5.1 nM(Ki)|CIAP1-BIR3:1.9 nM(Ki)

Xevinapant在小鼠、大鼠、非人类灵长类动物和狗中具有良好的药代动力学(PK)特性和口服生物利用度。在MDA-MB-231异种移植模型中，Xevinapant有效促进cIAP1降解和procaspase-8的处理，以及在100 mg/kg剂量下肿瘤组织中PARP的裂解，并且即使在200 mg/kg的剂量下也表现出良好的耐受性。Xevinapant在100 mg/kg剂量下显著抑制肿瘤生长，p值为0.0012。[1]

Xevinapant是一种Smac模拟物，能够在氢键和疏水作用上密切模仿AVPI肽与XIAP的结合，并与XIAP的W323有额外的疏水接触。相比Smac AVPI肽，Xevinapant对这些IAPs的敏感性更高，绑定亲和力提高了50-100倍。当浓度为1μM时，Xevinapant能完全恢复由500nM XIAP BIR3在无细胞系统中抑制的caspase-9活性。在MDA-MB-231细胞中，Xevinapant快速诱导cIAP1降解，并且能够拉下XIAP蛋白。Xevinapant对多种人类癌细胞系具有有效的抑制作用，在MDA-MB-231细胞和SK-OV-3卵巢细胞中表现出144和142nM的IC50，对正常类人乳腺上皮MCF-12F细胞和初级人正常前列腺上皮细胞具有低毒性。Xevinapant通过诱导caspase-3激活和PARP切割，在MDA-MB-231细胞中诱导凋亡。[1]

H2O:< 1 mg/mL (insoluble or slightly soluble);Ethanol:93 mg/mL (165.6 mM);DMSO:20 mg/mL (35.61 mM)

Cells are seeded in 96-well flat bottom cell culture plates at a density of (3-4) × 103 cells/well with AT-406 and incubated for 4 days. The rate of cell growth inhibition after treatment with different concentrations of AT-406 is determined by assaying with (2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium monosodium salt (WST-8). WST-8 is added to each well to a final concentration of 10%, and then the plates are incubated at 37 °C for 2−3 hours. The absorbance of the samples is measured at 450 nm using a TECAN ULTRA reader. Concentration of AT-406 that inhibited cell growth by 50% (IC50) is calculated by comparing absorbance in the untreated cells and the cells treated with AT-406. (Only for Reference)