Design, synthesis and biological evaluation of nuclear receptor-degradation inducers
Design, synthesis and biological evaluation of nuclear receptor-degradation inducers
复制标题
DOI：
10.1016/j.bmc.2011.09.041
复制
发表时间：
2011-11-15
影响因子：
3.5
通讯作者：
Hashimoto, Yuichi
中科院分区：
文献类型：
--
作者：
Itoh, Yukihiro;Kitaguchi, Risa;Hashimoto, Yuichi
调节核受体功能的化合物(S)在生物学研究中很有用，也是候选的治疗剂。大多数这类化合物是激动剂或拮抗剂。另一方面，我们开发了特定的蛋白质降解诱导剂，我们将其命名为狙击手(特定的和非遗传的IAPs依赖的蛋白质擦除器)，用于选择性地降解目标蛋白质。狙击手是一种杂化分子，由目标蛋白的适当配体与凋亡抑制蛋白(IAPs)的配体组成，IAPs的目标是结合蛋白的多泛素化和蛋白酶体降解。我们认为，用狙击手敲除蛋白质是一种很有前途的调节NR功能的替代方法。在本研究中，我们设计并合成了针对维甲酸受体(RAR)、雌激素受体(ER)和雄激素受体(AR)的降解诱导剂。这些新合成的RAR、ER和AR狙击剂，分别为9、11和13，被证实显著降低了活细胞中相应的NRs水平。(C)2011爱思唯尔有限公司。保留所有权利。
Compounds that regulate the function(s) of nuclear receptors (NRs) are useful for biological studies and as candidate therapeutic agents. Most such compounds are agonists or antagonists. On the other hand, we have developed specific protein degradation inducers, which we designated as SNIPERs (Specific and Nongenetic IAPs-dependent Protein ERasers), for selective degradation of target proteins. SNIPERs are hybrid molecules consisting of an appropriate ligand for the protein of interest, coupled to a ligand for inhibitor of apoptosis proteins (IAPs), which target the bound protein for polyubiquitination and proteasomal degradation. We considered that protein knockdown with SNIPERs would be a promising alternative approach for modulating NR function. In this study, we designed and synthesized degradation inducers targeting retinoic acid receptor (RAR), estrogen receptor (ER), and androgen receptor (AR). These newly synthesized RAR, ER, and AR SNIPERs, 9, 11, and 13, respectively, were confirmed to significantly reduce the levels of the corresponding NRs in live cells. (C) 2011 Elsevier Ltd. All rights reserved.