Background
Birinapant (TL32711) is a SMAC mimetic designed to specifically target cIAP1 and cIAP2 for degradation[1]. the binding constants (K d) of Birinapant (TL32711) for XIAP and cIAP1 were determined to be 45 and[3].
When Birinapant (TL32711) was combined with TNF-α, strong combination activity, that is, neither compound was effective individually but the combination was highly effective, was observed in 12 of 18 cell lines.Birinapant (TL32711) combined with TNF-α inhibited the growth of a melanoma cell line with acquired resistance to BRAF inhibition to the same extent as in the parental cell line[1]. When investigated the role of Birinapant (TL32711) in radiosensitization of glioblastoma cells, Birinapant (TL32711) can enhance the radiosensitivity of glioblastoma cell lines in cell-based assays and tumor models via radiation-induced TNF-α[4]. Combination of Birinapant (TL32711) and TNFα induced sub-G0 DNA fragmentation in sensitive lines and Birinapant (TL32711) alone also induced significant G2-M cell-cycle arrest and cell death in UM-SCC-46 cells[6]. Birinapant (TL32711) induced death receptor-/caspase-8-mediated apoptosis in AML cells, including in AML stem/progenitor cells, but not in normal CD34(+) cells[7].
Birinapant (TL32711) significantly improved the survival rate of endotoxemic mice and attenuated LPS-induced liver pathologic damage and inflammatory response. IL-1 and TNF-α levels in the serum were markedly decreased in Birinapant (TL32711) pretreatment mice compared with control mice .The cellular inhibitor of apoptosis protein 1 (cIAP1) expression in liver resident macrophage (Kupffer cells, KCs) was significantly decreased in the Birinapant (TL32711) group compared to the Vehicle group[2].
参考文献:
[1]. Krepler C, Chunduru SK, et,al. The novel SMAC mimetic birinapant exhibits potent activity against human melanoma cells. Clin Cancer Res. 2013 Apr 1;19(7):1784-94. doi: 10.1158/1078-0432.CCR-12-2518. Epub 2013 Feb 12. PMID: 23403634; PMCID: PMC3618495.
[2]. Liu H, Liao R, 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. Immunol Lett. 2017 May;185:79-83. doi: 10.1016/j.imlet.2017.02.016. Epub 2017 Mar 9. PMID: 28286228.
[3]. Allensworth JL, Sauer SJ, 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. Breast Cancer Res Treat. 2013 Jan;137(2):359-71. doi: 10.1007/s10549-012-2352-6. Epub 2012 Dec 7. PMID: 23225169.
[4]. Cerna D, Lim B, A et,al.SMAC Mimetic/IAP Inhibitor Birinapant Enhances Radiosensitivity of Glioblastoma Multiforme. Radiat Res. 2021 Jun 1;195(6):549-560. doi: 10.1667/RADE-20-00171.1. PMID: 33826739.
[5]. Zhu DL, Shuai LY. Effects of Birinapant on Proliferation and Invasion of MGC-803 Gastric Cancer Cells and Mechanism Underlying These Effects. Bull Exp Biol Med. 2021 May;171(1):56-61. doi: 10.1007/s10517-021-05172-w. Epub 2021 May 29. PMID: 34050412.
[6]. Eytan DF, Snow GE, et,al. SMAC Mimetic Birinapant plus Radiation Eradicates Human Head and Neck Cancers with Genomic Amplifications of Cell Death Genes FADD and BIRC2. Cancer Res. 2016 Sep 15;76(18):5442-5454. doi: 10.1158/0008-5472.CAN-15-3317. Epub 2016 Jul 28. PMID: 27469115; PMCID: PMC5026594.
[7]. Carter BZ, Mak PY, et,al. Synergistic targeting of AML stem/progenitor cells with IAP antagonist birinapant and demethylating agents. J Natl Cancer Inst. 2014 Feb;106(2):djt440. doi: 10.1093/jnci/djt440. PMID: 24526787; PMCID: PMC3952202.
Birinapant (TL32711) 是一种 SMAC 模拟物，旨在专门针对 cIAP1 和 cIAP2 进行降解[1]。 Birinapant (TL32711) 对 XIAP 和 cIAP1 的结合常数 (K d) 被确定为 45 和[3]。
当 Birinapant (TL32711) 与 TNF-α 联合使用时，在 18 种细胞系中的 12 种细胞系中观察到很强的联合活性，即两种化合物单独使用均无效，但联合使用非常有效。Birinapant (TL32711) 与 TNF 联合使用-α 对 BRAF 抑制具有获得性抗性的黑色素瘤细胞系的生长的抑制程度与亲本细胞系相同[1]。当研究 Birinapant (TL32711) 在胶质母细胞瘤细胞放射增敏中的作用时，Birinapant (TL32711) 可以通过辐射诱导的 TNF-α 增强胶质母细胞瘤细胞系在基于细胞的检测和肿瘤模型中的放射敏感性[4]。 Birinapant (TL32711) 和 TNFα 的组合在敏感细胞系中诱导亚 G0 DNA 片段化，单独使用 Birinapant (TL32711) 也在 UM-SCC-46 细胞中诱导显着的 G2-M 细胞周期停滞和细胞死亡 [6]。 Birinapant (TL32711) 在 AML 细胞（包括 AML 干细胞/祖细胞）中诱导死亡受体/caspase-8 介导的细胞凋亡，但在正常 CD34(+) 细胞中没有这种作用[7]。
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Birinapant (TL32711) 显着提高了内毒素血症小鼠的存活率，并减轻了 LPS 诱导的肝脏病理损伤和炎症反应。与对照小鼠相比，Birinapant (TL32711) 预处理小鼠血清中的 IL-1 和 TNF-α 水平显着降低。肝驻留巨噬细胞（Kupffer 细胞，KCs）中细胞凋亡蛋白 1 (cIAP1) 的表达显着降低Birinapant (TL32711) 组与载体组的比较[2]。
Protocol
| IAP binding affinity of Birinapant (TL32711)[1]: |
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Preparation Method
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A fluorescence polarization assay was used to determine the dissociation constants (K d) of Smac mimetics Birinapant (TL32711) and GT13402 for XIAP and cIAP1 by monitoring the decrease in fluorescence polarization signal due to competitive displacement of an FP peptide from the BIR3/FP peptide binary complex.
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Applications
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The binding constants (K d) of Birinapant (TL32711) for XIAP and cIAP1 were determined to be 45 and
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| Cell experiment [2]: |
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Cell lines
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451Lu and WM1366 melanoma cells
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Preparation Method
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Cells were treated with Birinapant (TL32711) 1 μmol/L in combination with TNF-α 1 ng/mL. Cells were then incubated for 72 hours in the presence or absence of Necrostatin-1 a RIP1 kinase inhibitor. Proliferation was assessed using the MTS assay.
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Reaction Conditions
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1 μmol/L Birinapant (TL32711) for 72 hours
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Applications
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The majority of cell lines exhibited strong combination activity of Birinapant (TL32711) and TNF-α.
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| Animal experiment [3]: |
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Animal models
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Male C57BL/6J mice aged 8 week old, weighing 21 ± 1.3g
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Preparation Method
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Before the LPS administration, mice were injected intraperitoneally with Birinapant (TL32711) (30 mg/kg body weight, Birinapant (TL32711) group) either vehicle control (vehicle group) for 24 h. Birinapant (TL32711) was dissolved in 12.5% Captisol in distilled water. Twenty-four mice in each group were euthanized and the samples of the liver and blood were harvested at 0, 6, 12 and 24 h after LPS challleage.
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Dosage form
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30 mg/kg Birinapant (TL32711) ip. for 24 h.
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Applications
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Birinapant (TL32711) pretreatment significantly improved mice survival.
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参考文献:
[1]. Allensworth JL, Sauer SJ, 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. Breast Cancer Res Treat. 2013 Jan;137(2):359-71. doi: 10.1007/s10549-012-2352-6. Epub 2012 Dec 7. PMID: 23225169.
[2]. Krepler C, Chunduru SK, et,al. The novel SMAC mimetic birinapant exhibits potent activity against human melanoma cells. Clin Cancer Res. 2013 Apr 1;19(7):1784-94. doi: 10.1158/1078-0432.CCR-12-2518. Epub 2013 Feb 12. PMID: 23403634; PMCID: PMC3618495.
[3]. Liu H, Liao R, 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. Immunol Lett. 2017 May;185:79-83. doi: 10.1016/j.imlet.2017.02.016. Epub 2017 Mar 9. PMID: 28286228.
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