Discovery of potent antagonists of the antiapoptotic protein XIAP for the treatment of cancer
Discovery of potent antagonists of the antiapoptotic protein XIAP for the treatment of cancer
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DOI：
10.1021/jm040037k
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发表时间：
2004-08-26
影响因子：
7.3
通讯作者：
Fesik, SW
中科院分区：
文献类型：
--
作者：
Oost, TK;Sun, CH;Fesik, SW
细胞凋亡抑制剂 (IAP) 蛋白在许多癌症中过度表达，并与肿瘤生长、发病机制以及对化疗或放疗的耐药性有关。基于与 X 连接 IAP (XIAP) 的 BIR3 结构域复合的 SMAC 肽的 NMR 结构，发现了一系列新型 XIAP 拮抗剂。该系列中最有效的化合物以个位数纳摩尔亲和力与 XIAP 的杆状病毒 IAP 重复 3 (BIR3) 结构域结合，并促进多种人类癌细胞系的细胞死亡。在 MDA-MB-231 乳腺癌小鼠异种移植模型中，这些 XIAP 拮抗剂抑制了肿瘤的生长。仅表现出与 XIAP-BIR3 结构域弱结合的紧密结构类似物在细胞测定中无活性，并且仅表现出边缘的体内活性。我们的结果与 XIAP BIR3 结构域的配体通过释放半胱天冬酶诱导细胞凋亡的机制一致。本研究验证了 XIAP 的 BIR3 结构域作为靶点，并支持使用小分子 XIAP 拮抗剂作为过度表达 XIAP 的癌症的潜在疗法。
Inhibitor of apoptosis (IAP) proteins are overexpressed in many cancers and have been implicated in tumor growth, pathogenesis, and resistance to chemo- or radiotherapy. On the basis of the NMR structure of a SMAC peptide complexed with the BIR3 domain of X-linked IAP (XIAP), a novel series of XIAP antagonists was discovered. The most potent compounds in this series bind to the baculovirus IAP repeat 3 (BIR3) domain of XIAP with single-digit nanomolar affinity and promote cell death in several human cancer cell lines. In a MDA-MB-231 breast cancer mouse xenograft model, these XIAP antagonists inhibited the growth of tumors. Close structural analogues that showed only weak binding to the XIAP-BIR3 domain were inactive in the cellular assays and showed only marginal in vivo activity. Our results are consistent with a mechanism in which ligands for the BIR3 domain of XIAP induce apoptosis by freeing up caspases. The present study validates the BIR3 domain of XIAP as a target and supports the use of small molecule XIAP antagonists as a potential therapy for cancers that overexpress XIAP.