Birinapant (TL32711), a Bivalent SMAC Mimetic, Targets TRAF2-Associated cIAPs, Abrogates TNF-Induced NF-kB Activation, and Is Active in Patient-Derived Xenograft Models
Birinapant (TL32711), a Bivalent SMAC Mimetic, Targets TRAF2-Associated cIAPs, Abrogates TNF-Induced NF-kB Activation, and Is Active in Patient-Derived Xenograft Models
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DOI：
10.1158/1535-7163.mct-13-0798
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发表时间：
2014-04-01
影响因子：
5.7
通讯作者：
Chunduru, Srinivas K.
中科院分区：
文献类型：
--
作者：
Benetatos, Christopher A.;Mitsuuchi, Yasuhiro;Chunduru, Srinivas K.
细胞凋亡抗性的获得是癌症发展中的基本事件。癌细胞逃避凋亡的机制之一是凋亡抑制剂（IAP）蛋白的失调。IAP的活性由内源性IAP拮抗剂如SMAC（也称为DIABLO）调节。SMAC对IAP蛋白的拮抗作用通过SMAC的N-末端四肽（AVPI）与IAP的选定BIR结构域的结合而发生。模拟SMAC的AVPI基序的小分子化合物已被设计用于克服IAP介导的癌细胞凋亡抗性。在这里，我们报告了birinapant（TL 32711）的临床前表征，birinapant是一种二价SMAC模拟化合物，目前正在临床试验中用于治疗癌症。Birinapant在体外与cIAP 1、cIAP 2、XIAP的BIR 3结构域和ML-IAP的BIR结构域结合，并诱导完整细胞中cIAP 1和cIAP 2的自泛素化和蛋白酶体降解，导致形成RIPK 1：caspase-8复合物、caspase-8激活和诱导肿瘤细胞死亡。Birinapant优先靶向TRAF 2相关的cIAP 1和cIAP 2，随后抑制TNF诱导的NF-κ B活化。birinapant以TNF依赖性或TNF非依赖性方式增强了多种化疗癌症药物的活性。在多个原发性患者来源的异种移植模型中，birinapant在耐受良好的剂量下抑制肿瘤生长。这些结果支持birinapant与多种化疗的治疗组合，特别是那些可以诱导TNF分泌的治疗。Mol Cancer Ther; 13（4）; 867-79.（C）2014年AACR。
The acquisition of apoptosis resistance is a fundamental event in cancer development. Among the mechanisms used by cancer cells to evade apoptosis is the dysregulation of inhibitor of apoptosis (IAP) proteins. The activity of the IAPs is regulated by endogenous IAP antagonists such as SMAC ( also termed DIABLO). Antagonism of IAP proteins by SMAC occurs via binding of the N-terminal tetrapeptide (AVPI) of SMAC to selected BIR domains of the IAPs. Small molecule compounds that mimic the AVPI motif of SMAC have been designed to overcome IAP-mediated apoptosis resistance of cancer cells. Here, we report the preclinical characterization of birinapant (TL32711), a bivalent SMAC-mimetic compound currently in clinical trials for the treatment of cancer. Birinapant bound to the BIR3 domains of cIAP1, cIAP2, XIAP, and the BIR domain of ML-IAP in vitro and induced the autoubiquitylation and proteasomal degradation of cIAP1 and cIAP2 in intact cells, which resulted in formation of a RIPK1:caspase-8 complex, caspase-8 activation, and induction of tumor cell death. Birinapant preferentially targeted the TRAF2-associated cIAP1 and cIAP2 with subsequent inhibition of TNF-induced NF-kB activation. The activity of a variety of chemotherapeutic cancer drugs was potentiated by birinapant both in a TNF-dependent or TNF-independent manner. Tumor growth in multiple primary patient-derived xenotransplant models was inhibited by birinapant at well-tolerated doses. These results support the therapeutic combination of birinapant with multiple chemotherapies, in particular, those therapies that can induce TNF secretion. Mol Cancer Ther; 13(4); 867-79. (C)2014 AACR.