PROTAC targeted protein degraders: the past is prologue.
PROTAC targeted protein degraders: the past is prologue.
复制标题
DOI：
10.1038/s41573-021-00371-6
复制
发表时间：
2022-03
期刊：
影响因子：
--
通讯作者：
Crews CM
中科院分区：
文献类型：
--
作者：
Békés M;Langley DR;Crews CM
靶向蛋白质降解（TPD）是一种新兴的治疗方式，有可能解决致病蛋白质，这些蛋白质在历史上一直是传统小分子靶向的高度挑战。自报道利用泛素-蛋白酶体系统降解靶蛋白的蛋白水解靶向嵌合体（PROTAC）分子的概念以来的20年中，TPD已经从学术界转移到工业界，许多公司已经公开了临床前和早期临床开发的计划。随着2020年PROTAC分子针对两个成熟的癌症靶点的临床概念验证，该领域有望追求以前被认为“坚不可摧”的靶点。在这篇综述中，我们总结了PROTAC发现的前二十年，并评估了当前的形势，重点关注行业活动。然后，我们讨论了TPD未来的关键领域，包括建立TPD最适合的目标类别，扩大泛素连接酶的使用以实现精准医疗，并将模式扩展到肿瘤学之外。用蛋白水解靶向嵌合体（PROTAC）进行靶向蛋白质降解具有解决致病蛋白质的潜力，这些致病蛋白质在历史上对用常规小分子靶向具有高度挑战性。本文总结了PROTAC发现的前二十年，并讨论了这种治疗方式未来的关键领域，包括建立最适合的目标类别，并将其应用扩展到肿瘤学之外。
Targeted protein degradation (TPD) is an emerging therapeutic modality with the potential to tackle disease-causing proteins that have historically been highly challenging to target with conventional small molecules. In the 20 years since the concept of a proteolysis-targeting chimera (PROTAC) molecule harnessing the ubiquitin–proteasome system to degrade a target protein was reported, TPD has moved from academia to industry, where numerous companies have disclosed programmes in preclinical and early clinical development. With clinical proof-of-concept for PROTAC molecules against two well-established cancer targets provided in 2020, the field is poised to pursue targets that were previously considered ‘undruggable’. In this Review, we summarize the first two decades of PROTAC discovery and assess the current landscape, with a focus on industry activity. We then discuss key areas for the future of TPD, including establishing the target classes for which TPD is most suitable, expanding the use of ubiquitin ligases to enable precision medicine and extending the modality beyond oncology. Targeted protein degradation with proteolysis-targeting chimeras (PROTACs) has the potential to tackle disease-causing proteins that have historically been highly challenging to target with conventional small molecules. This article summarizes the first two decades of PROTAC discovery and discusses key areas for the future of this therapeutic modality, including establishing the target classes for which it is most suitable and extending its application beyond oncology.
登录
查看更多内容
影响因子：
16.6
作者：
Alabi S;Jaime-Figueroa S;Yao Z;Gao Y;Hines J;Samarasinghe KTG;Vogt L;Rosen N;Crews CM
通讯作者：
Crews CM
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
影响因子：
64.8
作者：
Banik SM;Pedram K;Wisnovsky S;Ahn G;Riley NM;Bertozzi CR
通讯作者：
Bertozzi CR
影响因子：
16.8
作者：
Caussinus, Emmanuel;Kanca, Oguz;Affolter, Markus
通讯作者：
Affolter, Markus