TetraLogic Pharmaceuticals, Inc. , 343 Phoenixville Pike, Malvern, Pennsylvania 19355, United States.
J Med Chem. 2014 May 8;57(9):3666-77. doi: 10.1021/jm500176w. Epub 2014 Apr 15.
Birinapant (1) is a second-generation bivalent antagonist of IAP proteins that is currently undergoing clinical development for the treatment of cancer. Using a range of assays that evaluated cIAP1 stability and oligomeric state, we demonstrated that 1 stabilized the cIAP1-BUCR (BIR3-UBA-CARD-RING) dimer and promoted autoubiquitylation of cIAP1 in vitro. Smac-mimetic 1-induced loss of cIAPs correlated with inhibition of TNF-mediated NF-κB activation, caspase activation, and tumor cell killing. Many first-generation Smac-mimetics such as compound A (2) were poorly tolerated. Notably, animals that lack functional cIAP1, cIAP2, and XIAP are not viable, and 2 mimicked features of triple IAP knockout cells in vitro. The improved tolerability of 1 was associated with (i) decreased potency against cIAP2 and affinity for XIAP BIR3 and (ii) decreased ability to inhibit XIAP-dependent signaling pathways. The P2' position of 1 was critical to this differential activity, and this improved tolerability has allowed 1 to proceed into clinical studies.
比拉帕尼（1）是一种第二代双价 IAP 蛋白拮抗剂，目前正在临床开发用于癌症治疗。通过一系列评估 cIAP1 稳定性和寡聚状态的实验，我们证明 1 稳定了 cIAP1-BUCR（BIR3-UBA-CARD-RING）二聚体，并促进了 cIAP1 的自体泛素化。Smac 模拟物 1 诱导的 cIAPs 丢失与抑制 TNF 介导的 NF-κB 激活、半胱天冬酶激活和肿瘤细胞杀伤相关。许多第一代 Smac 模拟物，如化合物 A（2），耐受性较差。值得注意的是，缺乏功能性 cIAP1、cIAP2 和 XIAP 的动物无法存活，而 2 在体外模拟了三重 IAP 敲除细胞的特征。1 的耐受性提高与（i）对 cIAP2 的效力降低和对 XIAP BIR3 的亲和力降低，以及（ii）抑制 XIAP 依赖性信号通路的能力降低有关。1 的 P2' 位置对此差异活性至关重要，这种提高的耐受性使 1 能够进入临床研究。
