Xevinapant

1071992-99-8

561.71

DMSO : >= 100 mg/mL (178.03 mM)

Apoptosis

Xevinapant (AT-406) is a potent and orally bioavailable Smac mimetic and an antagonist of IAPs, and it binds to XIAP, cIAP1, and cIAP2 proteins with K_i of 66.4, 1.9, and 5.1 nM, respectively. IC50 & Target: Ki: 66.4 nM (XIAP), 1.9 nM (cIAP1), 5.1 nM (cIAP2) In Vitro: Xevinapant mimic closely the AVPI peptide in both hydrogen bonding and hydrophobic interactions with XIAP, with additional hydrophobic contacts with W323 of XIAP. Xevinapant is more sensitive to these IAPs than Smac AVPI peptide with 50-100 fold binding affinities. Xevinapant (1 uM) completely restores the activity of caspase-9, which is suppressed by 500 nM XIAP BIR3 in a cell-free system. In MDA-MB-231 cell, Xevinapant induces rapid cellular cIAP1 degradation and also pulls down the cellular XIAP protein. Xevinapant effectively inhibits lots of human cancer cell lines and shows IC₅₀ of 144 and 142 nM in MDA-MB-231 cell and SK-OV-3 ovarian cell, with low toxicity against normal-like human breast epithelial MCF-12F cells and primary human normal prostate epithelial cells. Xevinapant induces apoptosis in MDA-MB-231 cell by inducing activation of caspase-3 and cleavage of PARP^[1]. Xevinapant displays single agent activity in ovarian cancer cell lines. The IC₅₀ values of AT-406 in these ovarian cancer cells range from 0.05-0.5 ug/mL. Xevinapant exhibits anti-ovarian cancer efficacy both as a single agent and in combination with carboplatin. Xevinapant (30 ug/mL) induced degradation of XIAP in the drug sensitive ovarian cancer cell lines^[2]. In Vivo: Xevinapant has good pharmacokinetic properties and oral bioavailability in mice, rats, non-human primates, and dogs. In the MDA-MB-231 xenograft, Xevinapant effectively induces cIAP1 degradation and processing of procaspase-8, cleavage of PARP in tumor tissues at 100 mg/kg with well toleration even at 200 mg/kg. Xevinapant induces significant tumor growth inhibition with p of 0.0012 at 100 mg/kg^[2]. Xevinapant (30, 100 mg/kg, p.o.) decreases the plasma and tumor in tumor-bearing mice^[3].