Development of Chimeric Molecules That Degrade the Estrogen Receptor Using Decoy Oligonucleotide Ligands
Development of Chimeric Molecules That Degrade the Estrogen Receptor Using Decoy Oligonucleotide Ligands
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使用诱饵寡核苷酸配体开发降解雌激素受体的嵌合分子
DOI：
10.1021/acsmedchemlett.1c00629
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
Demizu Y.
中科院分区：
文献类型：
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作者：
Naganuma M;Ohoka N;Tsuji G;Tsujimura H;Matsuno K;Inoue T;Naito M;Demizu Y.
利用嵌合小分子，如靶向蛋白水解嵌合体（PROTACs）和凋亡蛋白特异性和非遗传抑制剂（IAP）依赖性蛋白清除剂（SNIPERs），作为一种通过泛素-蛋白酶体系统（UPS）降解细胞内靶蛋白的方法，引起了人们的关注。这些嵌合分子利用可以与蛋白质结合的小分子靶向多种蛋白质。然而，在缺乏合适的靶蛋白小分子配体（如转录因子）的情况下，很难开发出这种降解剂。因此，我们构建了由一个诱饵寡核苷酸组成的嵌合分子elcl - er (dec)，该诱饵寡核苷酸可以通过点击反应结合雌激素受体α (ERα)和IAP配体LCL161 （LCL）。发现LCL-ER（dec）可通过UPS选择性降解ERα。这些发现将适用于开发针对不同tf的其他寡核苷酸型降解物。
Targeted protein degradation using chimeric small molecules, such as proteolysis-targeting chimeras (PROTACs) and specific and nongenetic inhibitors of apoptosis protein (IAP)-dependent protein erasers (SNIPERs), has attracted attention as a method for degrading intracellular target proteins via the ubiquitin-proteasome system (UPS). These chimeric molecules target a variety of proteins using small molecules that can bind to the proteins. However, it is difficult to develop such degraders in the absence of suitable small-molecule ligands for the target proteins, such as for transcription factors (TFs). Therefore, we constructed the chimeric moleculeLCL-ER(dec), which consists of a decoy oligonucleotide that can bind to estrogen receptor α (ERα) and an IAP ligand, LCL161 (LCL), in a click reaction.LCL-ER(dec)was found to selectively degrade ERα via the UPS. These findings will be applicable to the development of other oligonucleotide-type degraders that target different TFs.