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Cited by 146Protein Degradation and InhibitorsChemical Synthesis and AnalysisUbiquitin and proteasome pathways

Characteristic roadmap of linker governs the rational design of PROTACs

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Dong, Yawen, Ma, Tingting, Xu, Ting, Feng, Zhangyan, Li, Yonggui, Song, Lingling, Yao, Xiaojun, Ashby, Charles R. +1 more·2024·Acta Pharmaceutica Sinica B
DOI 10.1016/j.apsb.2024.04.007PMC PMC11544172
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Abstract

Proteolysis targeting chimera (PROTAC) technology represents a groundbreaking development in drug discovery, leveraging the ubiquitin‒proteasome system to specifically degrade proteins responsible for the disease. PROTAC is characterized by its unique heterobifunctional structure, which comprises two functional domains connected by a linker. The linker plays a pivotal role in determining PROTAC's biodegradative efficacy. Advanced and rationally designed functional linkers for PROTAC are under development. Nonetheless, the correlation between linker characteristics and PROTAC efficacy remains under-investigated. Consequently, this study will present a multidisciplinary analysis of PROTAC linkers and their impact on efficacy, thereby guiding the rational design of linkers. We will primarily discuss the structural types and characteristics of PROTAC linkers, and the optimization strategies used for their rational design. Furthermore, we will discuss how factors like linker length, group type, flexibility, and linkage site affect the biodegradation efficiency of PROTACs. We believe that this work will contribute towards the advancement of rational linker design in the PROTAC research area.

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Cited by

Sorted by citations

Authors
Dong, Y., Ma, T., Xu, T., Feng, Z., Li, Y., Song, L., Yao, X., Ashby, C. R., & Hao, G.-F.
Affiliations
  • Guizhou University (CN)
  • Macao Polytechnic University (MO)
  • St. John's University (US)
Corresponding author
  • Yao, Xiaojun
  • Ashby, Charles R.
  • Hao, Ge-Fei
ORCID
Venue
Acta Pharmaceutica Sinica B
Publisher
Elsevier BV
Published
2024-10
Volume
14
Issue
10
Pages
4266-4295
ISSN
2211-3835 (ISSN-L)
DOI
10.1016/j.apsb.2024.04.007
PMC
PMC11544172
OpenAlex
W4394726128
Cited by
146
References
25
Citations by year
2026: 66 · 2025: 66 · 2024: 14
FWCI
6.01
Type
journal article
Language
en
Open access
Licence
Locations
  • Acta Pharmaceutica Sinica B (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Natural Science Foundation of China (32125033, 32260688)
  • Guizhou University
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
Keywords
PROTACs, heterobifunctional linker, linker design, ubiquitin-proteasome system, protein degradation, linker length, linker flexibility, rational drug design

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