Discovery of small molecule ligands for the von Hippel-Lindau (VHL) E3 ligase and their use as inhibitors and PROTAC degraders.
Discovery of small molecule ligands for the von Hippel-Lindau (VHL) E3 ligase and their use as inhibitors and PROTAC degraders.
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DOI：
10.1039/d2cs00387b
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发表时间：
2022-10-03
影响因子：
46.2
通讯作者：
Ciulli, Alessio
中科院分区：
文献类型：
--
作者：
Diehl, Claudia J.;Ciulli, Alessio
von Hippel-Lindau（VHL）Cullin RING E3连接酶是泛素-蛋白酶体系统中的必需酶，其募集底物如缺氧诱导因子用于泛素化和随后的蛋白酶体降解。泛素-蛋白酶体途径可以使用蛋白水解靶向嵌合体（PROTAC）被劫持到非天然新底物蛋白，PROTAC是设计为同时结合E3连接酶和靶蛋白以诱导靶泛素化和降解的双功能分子。对E3连接酶具有良好结合亲和力的高质量小分子配体的可用性是PROTAC开发的基础。缺乏良好的E3连接酶配体作为开发PROTAC降解剂的起点最初是该领域发展的绊脚石。在此，旅程的小分子配体结合VHL的设计。我们涵盖了VHL配体的基于结构的设计，它们本身作为抑制剂的应用，以及它们在各种靶蛋白的合理设计的有效PROTAC降解剂中的实施。我们强调了关键的发现和学习，为靶向蛋白质降解的显着发展提供了坚实的基础，并提供了一个蓝图，设计新的配体E3连接酶超越VHL。本文综述了基于结构的小分子VHL配体的设计及其在PROTAC降解剂中作为VHL抑制剂和E3连接酶招募部分的应用。
The von Hippel-Lindau (VHL) Cullin RING E3 ligase is an essential enzyme in the ubiquitin-proteasome system that recruits substrates such as the hypoxia inducible factor for ubiquitination and subsequent proteasomal degradation. The ubiquitin-proteasome pathway can be hijacked toward non-native neo-substrate proteins using proteolysis targeting chimeras (PROTACs), bifunctional molecules designed to simultaneously bind to an E3 ligase and a target protein to induce target ubiquitination and degradation. The availability of high-quality small-molecule ligands with good binding affinity for E3 ligases is fundamental for PROTAC development. Lack of good E3 ligase ligands as starting points to develop PROTAC degraders was initially a stumbling block to the development of the field. Herein, the journey towards the design of small-molecule ligands binding to VHL is presented. We cover the structure-based design of VHL ligands, their application as inhibitors in their own right, and their implementation into rationally designed, potent PROTAC degraders of various target proteins. We highlight the key findings and learnings that have provided strong foundations for the remarkable development of targeted protein degradation, and that offer a blueprint for designing new ligands for E3 ligases beyond VHL. This review provides a comprehensive overview of the structure-based design of small-molecule VHL ligands and their applications as VHL inhibitors and E3 ligase recruiting moieties in PROTAC degraders.
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影响因子：
3.4
作者：
Cardote TA;Ciulli A
通讯作者：
Ciulli A
DOI：
10.1126/science.1249830
发表时间：
2014-10-31
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Baud MGJ;Lin-Shiao E;Cardote T;Tallant C;Pschibul A;Chan KH;Zengerle M;Garcia JR;Kwan TT;Ferguson FM;Ciulli A
通讯作者：
Ciulli A
影响因子：
7.3
作者：
Chan KH;Zengerle M;Testa A;Ciulli A
通讯作者：
Ciulli A
影响因子：
4
作者：
Buckley DL;Raina K;Darricarrere N;Hines J;Gustafson JL;Smith IE;Miah AH;Harling JD;Crews CM
通讯作者：
Crews CM
影响因子：
14.8
作者：
Bondeson DP;Mares A;Smith IE;Ko E;Campos S;Miah AH;Mulholland KE;Routly N;Buckley DL;Gustafson JL;Zinn N;Grandi P;Shimamura S;Bergamini G;Faelth-Savitski M;Bantscheff M;Cox C;Gordon DA;Willard RR;Flanagan JJ;Casillas LN;Votta BJ;den Besten W;Famm K;Kruidenier L;Carter PS;Harling JD;Churcher I;Crews CM
通讯作者：
Crews CM