Birinapant (TL32711) is a SMAC mimetic designed to specifically target cIAP1 and cIAP2 for degradation[1]. Birinapant rapidly degrades cIAPs and enables cytokines (TNFα, TRAIL) to activate the extrinsic apoptosis pathway, while Birinapant rapidly turns off the canonical NF-κB survival pathway, causing cancer cell death[2]. Birinapant has been widely used to inhibit the growth of various cancer cells and to increase the production of TNF[3].
In vitro, Birinapant treatment for 72 hours significantly inhibited the viability of MDA-MB-231 and A875 cells, with IC50 values of 10nM and 40nM, respectively[4]. Treatment with 1μM Birinapant for 24 hours significantly induced apoptosis in SUM190 cells, resulting in activation of caspase and NF-κB, as well as cleavage of PARP[5].
In vivo, Birinapant treatment via intraperitoneal injection at a dose of 30mg/kg, once a week for 2 weeks, significantly promoted apoptosis and inhibited the growth of subcutaneous hepatocellular carcinoma tumors in nude mice[6]. A single intraperitoneal injection of a 30mg/kg dose of Birinapant alleviated liver injury induced by lipopolysaccharide (LPS) in mice and increased the survival rate of mice within 72 hours[7]. A single intravenous injection of Birinapant at 30mg/kg for 24h alleviated lung injury induced by LPS in mice and reduced the production of pro-inflammatory cytokines[8].
References:
[1] Condon S M, Mitsuuchi Y, Deng Y, et al. Birinapant, a smac-mimetic with improved tolerability for the treatment of solid tumors and hematological malignancies[J]. 2014.
[2] Benetatos C A, Mitsuuchi Y, Burns J M, et al. Birinapant (TL32711), a bivalent SMAC mimetic, targets TRAF2-associated cIAPs, abrogates TNF-induced NF-κB activation, and is active in patient-derived xenograft models[J]. Molecular cancer therapeutics, 2014, 13(4): 867-879.
[3] Chang Y C, Cheung C H A. An updated review of smac mimetics, LCL161, birinapant, and GDC-0152 in cancer treatment[J]. Applied Sciences, 2020, 11(1): 335.
[4] Perez H L, Chaudhry C, Emanuel S L, et al. Discovery of potent heterodimeric antagonists of inhibitor of apoptosis proteins (IAPs) with sustained antitumor activity[J]. Journal of medicinal chemistry, 2015, 58(3): 1556-1562.
[5] Allensworth J L, Sauer S J, Lyerly H K, et al. Smac mimetic Birinapant induces apoptosis and enhances TRAIL potency in inflammatory breast cancer cells in an IAP-dependent and TNF-α-independent mechanism[J]. Breast cancer research and treatment, 2013, 137(2): 359-371.
[6] Ding J, Qin D, Zhang Y, et al. SMAC mimetic birinapant inhibits hepatocellular carcinoma growth by activating the cIAP1/TRAF3 signaling pathway[J]. Molecular medicine reports, 2020, 21(3): 1251-1257.
[7] Liu H, Liao R, He K, et al. The smac mimetic birinapant attenuates lipopolysaccharide-induced liver injury by inhibiting the tumor necrosis factor receptor–associated factor 3 degradation in kupffer cells[J]. Immunology Letters, 2017, 185: 79-83.
[8] Hu H, Ma M, Li T, et al. The SMAC mimetic birinapant alleviates lipopolysaccharide-induced acute lung injury by inhibiting MAPK signaling[J]. Immunology Letters, 2023, 264: 31-35.