Birinapant, a Smac-Mimetic with Improved Tolerability for the Treatment of Solid Tumors and Hematological Malignancies
Birinapant, a Smac-Mimetic with Improved Tolerability for the Treatment of Solid Tumors and Hematological Malignancies
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DOI：
10.1021/jm500176w
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发表时间：
2014-05-08
影响因子：
7.3
通讯作者：
Chunduru, Srinivas K.
中科院分区：
文献类型：
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作者：
Condon, Stephen M.;Mitsuuchi, Yasuhiro;Chunduru, Srinivas K.
Birinapant（1）是IAP蛋白的第二代二价拮抗剂，目前正在进行癌症治疗的临床开发。使用一系列评估cIAP 1稳定性和寡聚状态的测定，我们证明了1在体外稳定cIAP 1-BUCR（BIR 3-UBA-CARD-RING）二聚体并促进cIAP 1的autoubiquitylation。Smac模拟物1诱导的cIAP损失与TNF介导的NF-κ B活化、半胱天冬酶活化和肿瘤细胞杀伤的抑制相关。许多第一代Smac模拟物如化合物A（2）耐受性差。值得注意的是，缺乏功能性cIAP 1、cIAP 2和XIAP的动物是不能存活的，并且2在体外模拟了三重IAP敲除细胞的特征。1的改善的耐受性与（i）针对cIAP 2的效力和对XIAP BIR 3的亲和力降低和（ii）抑制XIAP依赖性信号传导途径的能力降低相关。1的P-2'位置对于这种差异活性是关键的，并且这种改善的耐受性允许1进行临床研究。
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-kappa B 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 P-2' position of 1 was critical to this differential activity, and this improved tolerability has allowed 1 to proceed into clinical studies.