Targeted degradation of the aryl hydrocarbon receptor by the PROTAC approach: A useful chemical genetic tool
Targeted degradation of the aryl hydrocarbon receptor by the PROTAC approach: A useful chemical genetic tool
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DOI：
10.1002/cbic.200700438
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发表时间：
2007-11-23
期刊：
影响因子：
3.2
通讯作者：
Kim, Kyung-Bo
中科院分区：
文献类型：
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作者：
Lee, Hyosung;Puppala, Dinesh;Kim, Kyung-Bo
近年来，小分子已经成为许多生物过程研究的主要贡献者。由于具有生物活性的小分子往往通过抑制特定的蛋白质来发挥其活性，它们为研究靶蛋白在复杂的信号通路中的作用提供了有价值的分子探针。因此，这种小分子或“化学遗传学”方法，比经典的遗传方法更容易提供对靶生物事件的时间和空间控制，是对传统遗传方法的补充。[1-4]最近，Deshaies，Crews和他的同事开发了一种激动人心的化学遗传学方法，旨在诱导靶蛋白的降解，[5-8]，并被恰当地命名为PROTAC(蛋白质降解靶向嵌合体)。PROTAC是嵌合的小分子，通过细胞内泛素-蛋白酶体途径将目标蛋白降解(图1)。PROTAC分子由一个特定的E3泛素-连接酶识别基序组成，该识别基序与目标蛋白结合的配体，并将其招募到特定的E3-连接酶复合体，用于多泛素化和26S蛋白酶体随后的降解。与传统的通过与目标蛋白质直接或间接相互作用来抑制蛋白质功能的生物活性小分子不同，PROTAC分子通过消除(而不是简单地“抑制”蛋白质功能)来抑制蛋白质功能；因此，它们为蛋白质调节提供了一种替代策略。到目前为止，已经成功开发了几种主要针对核受体的PROTAC。[9，10]然而，尽管PROTAC具有巨大的潜力，但由于蛋白质-配体对的数量有限，PROTAC的广泛应用尚未完全实现。最近，一种类似的基于天然产物格尔达那霉素抑制热休克蛋白(HSP)-90能力的小分子方法被报道。这种方法会导致与HSP-90相互作用的核受体(如ER和AR)的降解。
In recent years, small molecules have been a major contributor to the investigation of many biological processes. Given that biologically active small molecules often exert their activities by inhibition of specific proteins, they provide valuable molecular probes for studying the role of targeted proteins in complex signaling pathways. Thus, this small-molecule or “chemical-genetics” approach, which easily affords more temporal and spatial control of targeted biological events than the classical genetic approach, is complementary to the conventional genetic approach.[1–4]Recently, an exciting chemical genetic approach, which was designed to induce degradation of targeted proteins, was developed by Deshaies, Crews, and colleagues,[5–8] and has been appropriately named PROTAC (PROteolysis TArgeting Chimera). PROTACs are chimeric small molecules that target proteins of interest for degradation by the intracellular ubiquitin–proteasome pathway (Figure 1). The PROTAC molecule is comprised of a specific E3 ubiquitin-ligase recognition motif linked to a ligand that binds to the targeted protein, and recruits it to the specific E3-ligase complex for multiubiquitination and subsequent degradation by the 26S proteasome. Unlike conventional bioactive small molecules that inhibit protein function by direct or indirect interactions with the targeted protein, PROTAC molecules inhibit protein function by elimination (rather than by simple “inhibition” of protein function); thereby they provide an alternative strategy for protein modulation. Thus far, several PROTACs, mostly aimed at nuclear receptors, have been successfully developed.[9, 10] However, despite its great potential, the widespread applications of PROTACs are yet to be fully realized, due largely to a limited number of protein–ligand pairs. Recently, a similar small-molecule approach based on the ability of the natural product geldanamycin to inhibit heat shock protein (HSP)-90 has been reported. This approach induces degradation of nuclear receptors that interact with HSP-90 (eg, ER and AR).[11–13] However, this geldanamy-