Targeted Protein Degradation by Small Molecules

Bondeson, Daniel P.; Crews, Craig M.

doi:10.1146/annurev-pharmtox-010715-103507

Cited by 207Protein Degradation and InhibitorsUbiquitin and proteasome pathwaysChemical Synthesis and Analysis

The DOI matches its Crossref record; 112 of the 112 references it cites were found in a registry or an index.

Targeted Protein Degradation by Small Molecules

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Bondeson, Daniel P., Crews, Craig M.·2017·Annual Review of Pharmacology and Toxicology

DOI 10.1146/annurev-pharmtox-010715-103507PMC PMC5586045

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Abstract

Protein homeostasis networks are highly regulated systems responsible for maintaining the health and productivity of cells. Whereas therapeutics have been developed to disrupt protein homeostasis, more recently identified techniques have been used to repurpose homeostatic networks to effect degradation of disease-relevant proteins. Here, we review recent advances in the use of small molecules to degrade proteins in a selective manner. First, we highlight all-small-molecule techniques with direct clinical application. Second, we describe techniques that may find broader acceptance in the biomedical research community that require little or no synthetic chemistry. In addition to serving as innovative research tools, these new approaches to control intracellular protein levels offer the potential to develop novel therapeutics targeting proteins that are not currently pharmaceutically vulnerable.

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The catalytic nature of PROTAC can achieve and maintain enhanced target degradation at low doses.
“Moreover, the catalytic nature of PROTAC can achieve and maintain enhanced target degradation at low doses (23, 25).”
From Small-molecule PROTAC mediates targeted protein degradation to treat STAT3-dependent epithelial cancer (2022) · cites this paper as [25]
The PROTACs > Next-Generation PROTACs section reports near-complete target-protein removal at concentrations as low as 5 nM, supporting effective degradation at low concentrations. Our copy does not establish that this effect is maintained over time or explicitly attribute it to PROTACs’ catalytic nature. (LLM, conf=0.83)
Experimental — accuracy not yet measured
PROTACs can achieve high cellular potency due to their catalytic rather than occupancy-based mechanism of action.
“PROTACs can achieve high cellular potency due to their catalytic rather than occupancy-based mechanism of action 11,14,22”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [22]

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Authors: Bondeson, D. P., & Crews, C. M.
Affiliations: Yale University (US)
Corresponding author: Crews, Craig M.
ORCID: Bondeson, Daniel P.
Crews, Craig M.
Venue: Annual Review of Pharmacology and Toxicology
Publisher: Annual Reviews
Published: 2017-01-06
Volume: 57
Issue: 1
Pages: 107-123
ISSN: 0362-1642 (ISSN-L)
1545-4304
DOI: 10.1146/annurev-pharmtox-010715-103507
PMC: PMC5586045
OpenAlex: W2530302741
Cited by: 207
References: 112
Citations by year: 2026: 25 · 2025: 34 · 2024: 15 · 2023: 17 · 2022: 17 · 2021: 24 · 2020: 22 · 2019: 32 · 2018: 13 · 2017: 7
FWCI: 1.60
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: The Annual Review of Pharmacology and Toxicology (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Institutes of Health
National Cancer Institute (F99CA212229, R35CA197589)
National Institute of General Medical Sciences (T32GM007223)
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
Physical Sciences › Chemistry › Organic Chemistry › Chemical Synthesis and Analysis
Keywords: targeted protein degradation, small molecules, proteostasis, selective protein degradation, drug repurposing, therapeutic target, research tools
MeSH terms: Animals, Humans, Oligopeptides, Proteins, Drug Delivery Systems, Small Molecule Libraries, Proteolysis

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