Description
AT-406 is an orally bioavailable Smac/DIABLO mimetic and antagonist of the inhibitor of apoptosis proteins (IAPs). It binds to XIAP, cIAP1, and cIAP2 proteins with K
i values of 66.4, 1.9, and 5.1 nM, respectively. It has been shown to inhibit cancer cell growth in various human cancer cell lines and to induce apoptosis in xenograft tumors in mice.
Uses
SM 406 is a potent and orally active antagonist of multiple inhibitor of apoptosis proteins (IAPs).
Uses
AT-406 is a potent IAP (inhibitor of apoptosis protein) inhibitor of XIAP, cIAP1, and cIAP2 with Ki of 66.4 nM, 1.9 nM, and 5.1 nM, respectively.
Biological Activity
Xevinapant (AT406, ARRY-334543, Debio1143, SM-406) is a potent Smac mimetic and an antagonist of IAP (inhibitor of apoptosis protein via E3 ubiquitin ligase), binding to XIAP-BIR3, cIAP1-BIR3 and cIAP2-BIR3 with Ki of 66.4 nM, 1.9 nM, and 5.1 nM, 50- to 100-fold higher affinities than the Smac AVPI peptide. Phase 1.
in vitro
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) 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.
in vivo
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.
References
schimmer a d. inhibitor of apoptosis proteins: translating basic knowledge into clinical practice[j]. cancer research, 2004, 64(20): 7183-7190.cai q, sun h, peng y, et al. a potent and orally active antagonist (sm-406/at-406) of multiple inhibitor of apoptosis proteins (iaps) in clinical development for cancer treatment[j]. journal of medicinal chemistry, 2011, 54(8): 2714-2726.zhang t, li y. et al. aphysiologically based pharmacokinetic and pharmacodynamic modeling of an antagonist (sm-406/at-406) of multiple inhibitor of apoptosis proteins (iaps) in a mouse xenograft model of human breast cancer. biopharm drug dispos. 2013 sep;34(6):348-59.hurwitz hi1, smith dc, et al. safety, pharmacokinetics, and pharmacodynamic properties of oral debio1143 (at-406) in patients with advanced cancer: results of a first-in-man study. cancer chemotherpharmacol. 2015 apr;75(4):851-9.
