AT-406 是一种有效的,可口服的 Smac 模拟物,为 IAPs 的拮抗剂,能够抑制 XIAP,cIAP1 和 cIAP2 蛋白,Ki 值分别为 66.4,1.9 和 5.1 nM。
Description | 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 Ki of 66.4, 1.9, and 5.1 nM, respectively. | ||||||||||||||||
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IC50 & Target | Ki: 66.4 nM (XIAP), 1.9 nM (cIAP1), 5.1 nM (cIAP2) | ||||||||||||||||
In Vitro | AT-406 mimic closely the AVPI peptide in both hydrogen bonding and hydrophobic interactions with XIAP, with additional hydrophobic contacts with W323 of XIAP. AT-406 is more sensitive to these IAPs than Smac AVPI peptide with 50-100 fold binding affinities. AT-406 (1 μM) 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, AT-406 induces rapid cellular cIAP1 degradation and also pulls down the cellular XIAP protein. AT-406 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. AT-406 induces apoptosis in MDA-MB-231 cell by inducing activation of caspase-3 and cleavage of PARP[1]. AT-406 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 µg/mL. AT-406 exhibits anti-ovarian cancer efficacy both as a single agent and in combination with carboplatin. AT-406 (30 μg/mL) induced degradation of XIAP in the drug sensitive ovarian cancer cell lines[2]. | ||||||||||||||||
In Vivo | AT-406 has good pharmacokinetic properties and oral bioavailability in mice, rats, non-human primates, and dogs. In the MDA-MB-231 xenograft, AT-406 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. AT-406 induces significant tumor growth inhibition with p of 0.0012 at 100 mg/kg[2]. SM-406 (30, 100 mg/kg, p.o.) decreases the plasma and tumor in tumor-bearing mice[3]. | ||||||||||||||||
Solvent & Solubility | In Vitro: 10 mM in DMSO Preparing Stock Solutions
* Please refer to the solubility information to select the appropriate solvent. | ||||||||||||||||
References | |
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