Protocols for Synthesis of and the Methods to Evaluate the Anticancer Effects
Protocols for Synthesis of and the Methods to Evaluate the Anticancer Effects
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合成方案和抗癌效果评价方法
DOI：
10.1007/978-1-0716-1665-9_18
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
Naito Mikihiko
中科院分区：
文献类型：
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作者：
Tsukumo Yoshinori;Tsuji Genichiro;Yokoo Hidetomo;Shibata Norihito;Ohoka Nobumichi;Demizu Yosuke;Naito Mikihiko
通过使用以蛋白水解靶向嵌合体为代表的嵌合小分子来诱导不可药物化的靶蛋白的降解是药物开发的有前途的策略。我们开发了一系列嵌合分子，称为“特异性和非遗传性凋亡蛋白（IAP）依赖性蛋白擦除器”（SNIPERs），招募IAP泛素连接酶诱导靶蛋白的降解。SNIPER还诱导一些IAP的降解，包括cIAP1和XIAP，它们是在许多癌症中过表达的抗凋亡蛋白。这种蛋白质降解剂具有独特的性质，在癌症治疗中可能特别有用。本章描述了（1）SNIPER化合物的设计和合成，（2）用于检测靶蛋白降解和泛素化的方法，以及（3）评价SNIPER抗肿瘤活性的方案。
Inducing degradation of undruggable target proteins by the use of chimeric small molecules, represented by proteolysis-targeting chimeras, is a promising strategy for drug development. We developed a series of chimeric molecules, termed “specific and nongenetic inhibitor of apoptosis protein (IAP)-dependent protein erasers” (SNIPERs) that recruit IAP ubiquitin ligases to induce degradation of target proteins. SNIPERs also induce degradation of some IAPs, including cIAP1 and XIAP, which are antiapoptotic proteins that are overexpressed in many cancers. Such protein degraders have unique properties that could be especially useful in cancer therapy. This chapter describes (1) the design and synthesis of SNIPER compounds, (2) the methods used for the detection of target protein degradation and ubiquitylation, and (3) the protocol to evaluate the antitumor activity of SNIPER.