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Cited by 869Protein Degradation and InhibitorsUbiquitin and proteasome pathwaysChemical Synthesis and Analysis

PROTACs: past, present and future

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Li, Ke, Crews, Craig M.·2022·Chemical Society Reviews
DOI 10.1039/d2cs00193dPMC PMC10237031
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Abstract

This review highlights important milestones in the evolution of PROTACs, briefly discusses recent lessons about targeted protein degradation, and conjectures on the efforts still needed to expand the toolbox for PROTAC discovery.

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  • Compared with traditional occupancy-based inhibitors, PROTACs offer advantages in dosing precision, side effect management, drug resistance prevention, and modulation of undruggable targets.

    “Compared with traditional occupancy-based inhibitors, PROTACs offer several advantages with respect to dosing precision, side effect management, drug resistance prevention, and the modulation of ‘undruggable’ targets21,22.”

    From An HDAC4-specific PROTAC degrader achieves radiation sensitization by enhancing ferroptosis in lung cancer (2026) · cites this paper as [21]

    The Abstract and Conclusions describe advantages over occupancy-driven inhibitors, including reduced dosing, potential reductions in toxicity, efficacy despite resistance mechanisms, and expanded target space. They do not establish more precise dosing or prevention of drug resistance: reduced dosing is not the same as dosing precision, and overcoming resistance is not the same as preventing it. The cited passages have section labels but no page numbers. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Li, K., & Crews, C. M.
Affiliations
Yale University (US)
Corresponding author
Crews, Craig M.
ORCID
Venue
Chemical Society Reviews
Publisher
Royal Society of Chemistry (RSC)
Published
2022
Volume
51
Issue
12
Pages
5214-5236
ISSN
  • 0306-0012 (ISSN-L)
  • 1460-4744
DOI
10.1039/d2cs00193d
PMC
PMC10237031
OpenAlex
W4282935215
Cited by
869
References
23
Citations by year
2026: 242 · 2025: 262 · 2024: 216 · 2023: 123 · 2022: 26
FWCI
16.30
Type
journal article
Language
en
Open access
Licence
rsc.li/journals-terms-of-use (am, 522 d)
Locations
  • Chemical Society Reviews (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • American Cancer Society (Research Professorship)
  • National Cancer Institute (NIH R01CA238570, NIH R35CA197589)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
Keywords
PROTACs, targeted protein degradation, E3 ubiquitin ligase, ubiquitin-proteasome system, heterobifunctional molecules, protein degradation, drug resistance, mechanism of action
MeSH terms
Ubiquitin-Protein Ligases, Proteasome Endopeptidase Complex, Ubiquitination, Proteolysis

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