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.
1 It has been shown to inhibit cancer cell growth in various human cancer cell lines and to induce apoptosis in xenograft tumors in mice.
1,2
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.
Uses
SM 406 is a potent and orally active antagonist of multiple inhibitor of apoptosis proteins (IAPs).
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.
