IC50: 17 and 108 nmol/L for GFPcIAP1 and GFP-cIAP2, respectively
Birinapant (TL32711) is a bivalent SMAC mimetic. Apoptosis resistance acquisition is a fundamental event in the development of cancer. Among the mechanisms is the dysregulation of inhibitor of apoptosis (IAP) proteins regulated by endogenous IAP antagonists such as SMAC. Drugs mimicing the SMAC have been designed to overcome IAP-mediated apoptosis resistance of cancer cells.
In vitro: Birinapant bound to BIR3 domains of cIAP1, cIAP2, XIAP, as well as the BIR domain of ML-IAP and induced the proteasomal degradation and autoubiquitylation of cIAP1 and cIAP2. Birinapant also targeted the TRAF2-associated cIAP1 and cIAP2 with subsequent inhibition of TNF-induced NF-kB activation .…show more content… These results supported the therapeutic combination of birinapant with multiple chemotherapies, especially, those therapies inducing TNF secretion .
Clinical trial: Phase 1 clinical trial of birinapant with one of standard chemotherapy regimens showed that birinapant did not exacerbate the toxicities commonly associated with any of these regimens. Fourteen subjects showed anti-tumor activity. One NSCLC subject had a CR and thirteen subjects with PRs, including anal cancer, CRC, gallbladder cancer, melanoma, and ovarian cancer