Two-headed PROTAC: an effective new tool for targeted protein degradation.
Two-headed PROTAC: an effective new tool for targeted protein degradation.
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DOI：
10.1002/cbic.201000222
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发表时间：
2010-07-26
期刊：
影响因子：
3.2
通讯作者：
Kim, Kyung-Bo
中科院分区：
文献类型：
--
作者：
Cyrus, Kedra;Wehenkel, Marie;Choi, Eun-Young;Swanson, Hollie;Kim, Kyung-Bo
多年来，可以调节特定细胞蛋白质功能的小分子越来越多地被用作探索复杂生物过程的分子探针。这种小分子方法是对经典遗传方法的补充，因此被恰当地称为“化学遗传学”。[1，2]通常，小分子调节剂通过结合目标蛋白并阻断其功能来发挥其活性，从而扰乱感兴趣的细胞信号通路。虽然小分子已被证明有助于探索蛋白质在特定疾病病因学中的功能，但它们也提供了有前途的治疗剂。因此，人们做出了许多努力来寻找调节蛋白质功能的新的小分子。[3]泛素-蛋白酶体系统(UPS)是所有真核细胞中蛋白质周转的主要通道。这种依赖泛素的蛋白分解涉及通过三种酶--E1、E2和E3的作用将多泛素链附着到底物上，标记该底物被26S蛋白酶体降解。[4]鉴于通过UPS调节蛋白质的动态平衡会导致目标蛋白质的破坏，这一蛋白质靶向过程需要仔细调节。E3泛素连接酶似乎是泛素化级联反应中底物特异性的主要来源，因为它们已经被证明直接和特异性地结合到底物上。
Over the years, small molecules that can modulate functions of specific cellular proteins have been used more frequently as molecular probes for the exploration of complex biological processes. This small-molecule approach is complementary to a classical genetic approach and thus is fittingly termed “chemical genetics.”[1, 2] Typically, small molecule modulators exert their activity by binding target proteins and blocking their functions, thereby perturbing cellular signaling pathways of interest. While small molecules have proven useful for probing the function of proteins in the etiology of a specific disease, they have also provided promising therapeutic agents. Thus, a great deal of efforts has been made to identify novel small molecules that modulate protein functions.[3]The ubiquitin-proteasome system (UPS) is the principle conduit for protein turnover in all eukaryotic cells. This ubiquitin-dependent proteolysis involves the attachment of polyubiquitin chains to a substrate via the actions of three enzymes, E1, E2, and E3, marking this substrate for degradation by the 26S proteasome.[4] Given that the regulation of protein homeostasis via the UPS leads to the destruction of targeted proteins, this protein targeting process needs to be carefully regulated. The E3 ubiquitin ligases appear to be the primary source of substrate specificity in the ubiquitination cascade, as they have been shown to bind directly and specifically to the substrate.[5, 6]
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