Induced protein degradation: an emerging drug discovery paradigm

Lai, Ashton C.; Crews, Craig M.

doi:10.1038/nrd.2016.211

Cited by 1,486Protein Degradation and InhibitorsUbiquitin and proteasome pathwaysChemical Synthesis and Analysis

Induced protein degradation: an emerging drug discovery paradigm

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Lai, Ashton C., Crews, Craig M.·2017·Nature Reviews Drug Discovery

DOI 10.1038/nrd.2016.211PMC PMC5684876

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Abstract

Small-molecule drug discovery has traditionally focused on occupancy of a binding site that directly affects protein function, and this approach typically precludes targeting proteins that lack such amenable sites. Furthermore, high systemic drug exposures may be needed to maintain sufficient target inhibition in vivo, increasing the risk of undesirable off-target effects. Induced protein degradation is an alternative approach that is event-driven: upon drug binding, the target protein is tagged for elimination. Emerging technologies based on proteolysis-targeting chimaeras (PROTACs) that exploit cellular quality control machinery to selectively degrade target proteins are attracting considerable attention in the pharmaceutical industry owing to the advantages they could offer over traditional small-molecule strategies. These advantages include the potential to reduce systemic drug exposure, the ability to counteract increased target protein expression that often accompanies inhibition of protein function and the potential ability to target proteins that are not currently therapeutically tractable, such as transcription factors, scaffolding and regulatory proteins.

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The PROTAC technique can aid small molecule inhibitors or peptides to exert better biological activities in vivo by linking the ubiquitin-proteasome system to induce degradation of targeted proteins.
“The PROTAC technique could aid small molecule inhibitors or peptides to exert better biological activities in vivo as PROTAC can link the ubiquitin-proteasome system to induce effective degradation of targeted proteins16.”
From A PROTAC peptide induces durable β-catenin degradation and suppresses Wnt-dependent intestinal cancer (2020) · cites this paper as [16]
The Small-molecule PROTACs section (§4; page not provided) explains that PROTACs recruit an E3 ligase to degrade a target and reports mouse-xenograft evidence of better in vivo efficacy than parent inhibitors. The Peptide-based PROTACs section (§4; page not provided) describes peptide-based degradation mainly in cells and notes poor cell penetration; it does not establish better in vivo activity for peptide-based PROTACs. (LLM, conf=0.86)
Experimental — accuracy not yet measured
PROTAC molecules exhibit improved therapeutic efficacy and minimized drug resistance because of the potential for unique catalytic recycling.
“Third, PROTAC molecules exhibit improved therapeutic efficacy and minimized drug resistance because of the potential for unique catalytic recycling (23, 24).”
From Small-molecule PROTAC mediates targeted protein degradation to treat STAT3-dependent epithelial cancer (2022) · cites this paper as [24]
The Small-molecule PROTACs section reports that non-covalent PROTACs act catalytically, may require less drug exposure, and showed superior efficacy to parent inhibitors in mouse tumor xenografts. It also says protein removal can counteract compensatory accumulation associated with inhibitors, but does not establish that catalytic recycling minimizes drug resistance or that improved therapeutic efficacy has been demonstrated clinically. (LLM, conf=0.86)
Experimental — accuracy not yet measured
A targeted protein degrader is a chimeric small molecule that recruits a target protein into proximity of an E3 ubiquitin ligase, promoting polyubiquitylation and degradation of the target via the ubiquitin proteasome system.
“A targeted protein degrader is a chimeric small molecule that recruits target protein into the proximity of an E3 ubiquitin ligase, which then promotes polyubiquitylation of the target, triggering its degradation via the ubiquitin proteasome system (88, 89).”
From Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy (2025) · cites this paper as [88]
PROTAC adopts event-driven pharmacology binding at any point within the structure of potential targets, unlike occupancy-mode small molecule inhibitors.
“Unlike the occupancy mode of small molecule inhibitors, which increase the risk of off-target effects, PROTAC adopts the pattern of “event-driven” pharmacology binding at any point within the structure of potential targets (23, 24).”
From Small-molecule PROTAC mediates targeted protein degradation to treat STAT3-dependent epithelial cancer (2022) · cites this paper as [24]
PROTACs are bivalent small molecules containing a ligand that recognizes a target protein linked to another ligand that recruits a specific E3 ubiquitin ligase.
“PROTACs are bivalent small molecules containing a ligand that recognizes a target protein linked to another ligand that recruits a specific E3 ubiquitin ligase29,30.”
From Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity (2020) · cites this paper as [30]

PROTAC binding induces proximity-induced ubiquitination of the target protein and its subsequent degradation by proteasomes.
“PROTAC binding induces proximity-induced ubiquitination of the target protein and its subsequent degradation by proteasomes.”
From Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity (2020) · cites this paper as [30]
PROTACs act catalytically to induce protein degradation in a sub-stoichiometric manner.
“Thus, PROTACs act catalytically to induce protein degradation in a sub-stoichiometric manner.”
From Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity (2020) · cites this paper as [30]
This increase is likely due to PROTACs' catalytical action to induce protein degradation in a sub-stoichiometric manner, and that their effect is not limited by equilibrium occupancy as are conventional inhibitors such as ABT263.
“This increase is likely due to PROTACs’ catalytical action to induce protein degradation in a sub-stoichiometric manner, and that their effect is not limited by equilibrium occupancy as are conventional inhibitors such as ABT263 (refs. 29,30).”
From Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity (2020) · cites this paper as [30]
Targeted protein degradation is an important complementation and alternative to inhibitor-based therapeutics.
“TPD has caused great excitement in drug discovery in recent years as an important complementation and alternative to inhibitor-based therapeutics.[10][11][12][13]16”
From Chasing molecular glue degraders: screening approaches (2022) · cites this paper as [10]
PROTACs are small molecules with two functional ends, one binding the protein of interest and the other binding an E3 ubiquitin ligase, bringing the ligase to the target protein, leading to its ubiquitination and degradation by the proteasome.
“PROTACs are small molecules with two functional ends, wherein one end binds to the protein of interest while the other binds to an E3 ubiquitin ligase (2, 3), bringing the ubiquitin ligase to the target protein, leading to its ubiquitination and subsequent degradation by the proteasome.”
From The drug efflux pump MDR1 promotes intrinsic and acquired resistance to PROTACs in cancer cells (2022) · cites this paper as [3]
CRBN expression is required for the anti-myeloma activity of lenalidomide.
“CRBN expression is required for the anti-myeloma activity of lenalidomide142.”
From Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide (2021) · cites this paper as [142]
PROTACs degrade proteins of interest in a sub-stoichiometric manner.
“PROTACs act catalytically to induce protein degradation in a sub-stoichiometric manner [1].”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [1]

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[58]Katerina S Evangelia P HSP90 Inhibitors: Current Development and Potential in Cancer Therapy Recent Patents on Anti-Cancer Drug Discovery 9 1 20 2014 23312026
[189]Demetri GD A. L. C. Von Mehren M Chmielowski B Bauer S Chow WA Rodenas E McKee K Grayzel DS Kang Y 2010 Gastrointestinal Cancers Symposium 2010

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Targeting BCR-ABL1 in Chronic Myeloid Leukemia by PROTAC-Mediated Targeted Protein Degradation
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PROTAC-DB: an online database of PROTACs
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Solution Conformations Shed Light on PROTAC Cell Permeability
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Authors: Lai, A. C., & Crews, C. M.
Affiliations: Yale University (US)
Corresponding author: Crews, Craig M.
ORCID: Crews, Craig M.
Venue: Nature Reviews Drug Discovery
Publisher: Springer Science and Business Media LLC
Published: 2016-11-25
Volume: 16
Issue: 2
Pages: 101-114
ISSN: 1474-1776 (ISSN-L)
1474-1784
DOI: 10.1038/nrd.2016.211
PMC: PMC5684876
OpenAlex: W2553908226
Cited by: 1,486
References: 219
Citations by year: 2026: 162 · 2025: 188 · 2024: 199 · 2023: 162 · 2022: 171 · 2021: 168 · 2020: 177 · 2019: 133 · 2018: 76 · 2017: 48
FWCI: 7.71
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
Locations: Nature Reviews Drug Discovery (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: National Institutes of Health
National Cancer Institute (R35CA197589)
National Institute of General Medical Sciences (T32GM007205)
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, small molecule drug discovery, cell quality control, selective protein degradation, off-target effects, drug exposure, transcription factors, scaffold proteins, regulatory proteins
MeSH terms: Animals, Humans, Protein Binding, Proteins, Proteomics, Mutant Chimeric Proteins, Small Molecule Libraries, Drug Discovery, High-Throughput Screening Assays

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Induced protein degradation: an emerging drug discovery paradigm

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