Small-molecule antagonists of apoptosis suppressor XIAP exhibit broad antitumor activity
Small-molecule antagonists of apoptosis suppressor XIAP exhibit broad antitumor activity
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DOI：
10.1016/s1535-6108(03)00332-5
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发表时间：
2004-01-01
期刊：
影响因子：
50.3
通讯作者：
Reed, JC
中科院分区：
文献类型：
--
作者：
Schimmer, AD;Welsh, K;Reed, JC
细胞凋亡抗性通常发生在癌症中，阻止Caspase家族细胞死亡蛋白酶的活化。XIAP是在许多癌症中过表达的半胱天冬酶的内源性抑制剂。我们开发了一种酶去阻遏试验，基于克服XIAP介导的Caspase-3抑制，并筛选了基于混合物的组合化学文库，用于逆转XIAP介导的Caspase-3抑制的化合物，鉴定了一类具有XIAP抑制活性的聚苯脲。这些化合物，但不是无活性的结构类似物，刺激增加半胱天冬酶活性，直接诱导培养中的许多类型的肿瘤细胞系的凋亡，并使癌细胞对化疗药物敏感。活性化合物还抑制小鼠异种移植模型中已建立的肿瘤的生长，同时对正常组织显示出很小的毒性。这些发现验证了IAP作为癌症药物发现的靶点。
Apoptosis resistance commonly occurs in cancers, preventing activation of Caspase family cell death proteases. XIAP is an endogenous inhibitor of Caspases overexpressed in many cancers. We developed an enzyme derepression assay, based on overcoming XIAP-mediated suppression of Caspase-3, and screened mixture-based combinatorial chemical libraries for compounds that reversed XIAP-mediated inhibition of Caspase-3, identifying a class of polyphenylureas with XIAP-inhibitory activity. These compounds, but not inactive structural analogs, stimulated increases in Caspase activity, directly induced apoptosis of many types of tumor cell lines in culture, and sensitized cancer cells to chemotherapeutic drugs. Active compounds also suppressed growth of established tumors in xenograft models in mice, while displaying little toxicity to normal tissues. These findings validate IAPs as targets for cancer drug discovery.