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An overview of PROTACs: a promising drug discovery paradigm

Proteolysis targeting chimeras (PROTACs) technology has emerged as a novel therapeutic paradigm in recent years. PROTACs are heterobifunctional molecules that degrade target proteins by hijacking the ubiquitin–proteasome system. Currently, about 20–25% of all protein targets are being studied, and m...

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Autores principales: Liu, Zi, Hu, Mingxing, Yang, Yu, Du, Chenghao, Zhou, Haoxuan, Liu, Chengyali, Chen, Yuanwei, Fan, Lei, Ma, Hongqun, Gong, Youling, Xie, Yongmei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Nature Singapore 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9763089/
https://www.ncbi.nlm.nih.gov/pubmed/36536188
http://dx.doi.org/10.1186/s43556-022-00112-0
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author Liu, Zi
Hu, Mingxing
Yang, Yu
Du, Chenghao
Zhou, Haoxuan
Liu, Chengyali
Chen, Yuanwei
Fan, Lei
Ma, Hongqun
Gong, Youling
Xie, Yongmei
author_facet Liu, Zi
Hu, Mingxing
Yang, Yu
Du, Chenghao
Zhou, Haoxuan
Liu, Chengyali
Chen, Yuanwei
Fan, Lei
Ma, Hongqun
Gong, Youling
Xie, Yongmei
author_sort Liu, Zi
collection PubMed
description Proteolysis targeting chimeras (PROTACs) technology has emerged as a novel therapeutic paradigm in recent years. PROTACs are heterobifunctional molecules that degrade target proteins by hijacking the ubiquitin–proteasome system. Currently, about 20–25% of all protein targets are being studied, and most works focus on their enzymatic functions. Unlike small molecules, PROTACs inhibit the whole biological function of the target protein by binding to the target protein and inducing subsequent proteasomal degradation. PROTACs compensate for limitations that transcription factors, nuclear proteins, and other scaffolding proteins are difficult to handle with traditional small-molecule inhibitors. Currently, PROTACs have successfully degraded diverse proteins, such as BTK, BRD4, AR, ER, STAT3, IRAK4, tau, etc. And ARV-110 and ARV-471 exhibited excellent efficacy in clinical II trials. However, what targets are appropriate for PROTAC technology to achieve better benefits than small-molecule inhibitors are not fully understood. And how to rationally design an efficient PROTACs and optimize it to be orally effective poses big challenges for researchers. In this review, we summarize the features of PROTAC technology, analyze the detail of general principles for designing efficient PROTACs, and discuss the typical application of PROTACs targeting different protein categories. In addition, we also introduce the progress of relevant clinical trial results of representative PROTACs and assess the challenges and limitations that PROTACs may face. Collectively, our studies provide references for further application of PROTACs.
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spelling pubmed-97630892022-12-20 An overview of PROTACs: a promising drug discovery paradigm Liu, Zi Hu, Mingxing Yang, Yu Du, Chenghao Zhou, Haoxuan Liu, Chengyali Chen, Yuanwei Fan, Lei Ma, Hongqun Gong, Youling Xie, Yongmei Mol Biomed Review Proteolysis targeting chimeras (PROTACs) technology has emerged as a novel therapeutic paradigm in recent years. PROTACs are heterobifunctional molecules that degrade target proteins by hijacking the ubiquitin–proteasome system. Currently, about 20–25% of all protein targets are being studied, and most works focus on their enzymatic functions. Unlike small molecules, PROTACs inhibit the whole biological function of the target protein by binding to the target protein and inducing subsequent proteasomal degradation. PROTACs compensate for limitations that transcription factors, nuclear proteins, and other scaffolding proteins are difficult to handle with traditional small-molecule inhibitors. Currently, PROTACs have successfully degraded diverse proteins, such as BTK, BRD4, AR, ER, STAT3, IRAK4, tau, etc. And ARV-110 and ARV-471 exhibited excellent efficacy in clinical II trials. However, what targets are appropriate for PROTAC technology to achieve better benefits than small-molecule inhibitors are not fully understood. And how to rationally design an efficient PROTACs and optimize it to be orally effective poses big challenges for researchers. In this review, we summarize the features of PROTAC technology, analyze the detail of general principles for designing efficient PROTACs, and discuss the typical application of PROTACs targeting different protein categories. In addition, we also introduce the progress of relevant clinical trial results of representative PROTACs and assess the challenges and limitations that PROTACs may face. Collectively, our studies provide references for further application of PROTACs. Springer Nature Singapore 2022-12-20 /pmc/articles/PMC9763089/ /pubmed/36536188 http://dx.doi.org/10.1186/s43556-022-00112-0 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Review
Liu, Zi
Hu, Mingxing
Yang, Yu
Du, Chenghao
Zhou, Haoxuan
Liu, Chengyali
Chen, Yuanwei
Fan, Lei
Ma, Hongqun
Gong, Youling
Xie, Yongmei
An overview of PROTACs: a promising drug discovery paradigm
title An overview of PROTACs: a promising drug discovery paradigm
title_full An overview of PROTACs: a promising drug discovery paradigm
title_fullStr An overview of PROTACs: a promising drug discovery paradigm
title_full_unstemmed An overview of PROTACs: a promising drug discovery paradigm
title_short An overview of PROTACs: a promising drug discovery paradigm
title_sort overview of protacs: a promising drug discovery paradigm
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9763089/
https://www.ncbi.nlm.nih.gov/pubmed/36536188
http://dx.doi.org/10.1186/s43556-022-00112-0
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