Birinapant

Birinapant (TL32711), a bivalent Smac mimetic, is a potent antagonist for XIAP and cIAP1 with K_ds of 45 nM and less than 1 nM, respectively. Birinapant (TL32711) induces the autoubiquitylation and proteasomal degradation of cIAP1 and cIAP2 in intact cells, which results in formation of a RIPK1: caspase-8 complex, caspase-8 activation, and induction of tumor cell death. Birinapant (TL32711) targets TRAF2-associated cIAPs and abrogates TNF-induced NF-κB activation. IC50 & Target: Kd: 45 nM (XIAP), <1 nM (cIAP1)^[1] In Vitro: Birinapant (TL32711) (30-10000 nM; 24 hours) significantly decreases the viability of SUM190 cells in a dose-dependent manner^[1].
Birinapant (TL32711) (30-1000 nM; 4 hours) shows a significant decrease in cIAP1 levels and enhanced PARP cleavage, and induces apoptosis^[1].
Birinapant (TL32711) binds with high affinity to the isolated BIR3 domains of cIAP1, cIAP2, and XIAP and the single BIR domain of ML-IAP and rapidly degrades TRAF2-bound cIAP1 and cIAP2 thereby inhibiting TNF-mediated NF-κB activation^[1]. In Vivo: Birinapant (TL32711) (30 mg/kg; i.p.; every third day (*5)) shows antitumor efficacy and are devoid of overt toxicity in preclinical models^[2].