AT406 (SM-406, ARRY-334543)1071992-99-8

AT-406(SM-406, ARRY-334543)
分子式：C32H43N5O4    分子量：561.71
 
產(chǎn)品描述
AT-406是有效的，擬Smac的，IAP(通過E3泛素連接酶起作用的凋亡蛋白抑制劑)拮抗劑, 與XIAP-BIR3, cIAP1-BIR3 和cIAP2-BIR3結(jié)合，Ki為66.4 nM, 1.9 nM, 和5.1 nM,比作用于Smac AVPI 肽親和力高50到100倍。
靶點(diǎn)
XIAP
cIAP1
cIAP2
     
IC50
66.4 nM (Ki)
1.9 nM (Ki)
5.1 nM (Ki)
     
體外研究
AT-406 is a Smac mimetic and appears to 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 (at 1 μM) compley 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.
體內(nèi)研究
AT-406 has good pharmacokinetic (PK) 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.
溶解性
DMSO 100 mg/mL，水 <1 mg/mL，乙醇 100 mg/mL
穩(wěn)定性
2年 -20°C粉狀，6月-80°C溶于DMSO