Small-Molecule Degraders beyond PROTACs—Challenges and Opportunities
Open accessAbstract
Targeted protein degradation (TPD) is a recent strategy, utilizing the cell's proteostasis machinery to deplete specific proteins. This represents a paradigm shift in early drug discovery, away from occupancy-driven to event-driven mechanisms.Recent efforts have focused on the development of proteolysis-targeting chimeras (PROTACs). These heterobifunctional molecules combine a target-specific binding moiety linked to an E3 ligase ligand and trigger selective ubiquitination of the target protein, marking it for proteasomal degradation. While these molecules can be highly efficacious, they generally have unfavorable physicochemical properties due to their large size.In contrast, smaller molecules that induce degradation could represent an attractive, simple option to overcoming the limitations of both traditional modulators and PROTACs. These molecules may have a range of mechanisms: recruitment of an E3 ligase (molecular glues), introduction of hydrophobic areas, or inducing local unfolding, each of which triggers degradation.We recently completed a high-throughput screen of 111,000 compounds in a cellular HiBiT assay in an effort to identify such molecules. Preliminary analysis indicates that we have been able to identify alternative small-molecule degraders. We highlight methods for triage, characterization, selectivity, and mode of action. In summary, we believe that these types of small-molecule degraders, which may possibly have more acceptable physicochemical properties than the inherently larger heterobifunctional molecules, are an exciting approach for inducing TPD, and we illustrate that a general screening approach can be successful in identifying useful start points for developing such molecules.
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The success of PROTACs in hijacking the UPS for TPD has motivated research into other classes of heterobifunctional molecules that depend on non-UPS pathways to degrade a POI.
“The success of proteolysis-targeting chimeras (PROTACs) in hijacking the ubiquitin–proteasome system (UPS) for targeted protein degradation (TPD) has motivated research into other classes of heterobifunctional molecules that depend on non-UPS pathways to degrade a protein of interest (POI)246,247.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [247]
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“Monovalent and bivalent degraders have been extensively reviewed elsewhere (Farnaby et al. 2021; Kastl et al. 2021; Békés et al. 2022; Konstantinidou and Arkin 2024; lemaitre et al. 2024; Robinson et al. 2024; tan et al. 2024; Zhong et al. 2024). in this review, we focus on molecular glue…”
- Authors
- Kastl, J. M., Davies, G., Godsman, E., & Holdgate, G. A.
- Affiliations
- AstraZeneca (United Kingdom) (GB)
- Corresponding author
- Kastl, Johanna M.
- Venue
- SLAS Discovery
- Publisher
- Elsevier BV
- Published
- 2021-04
- Volume
- 26
- Issue
- 4
- Pages
- 524-533
- ISSN
- 2472-5552 (ISSN-L)
- OpenAlex
- W3133088664
- Cited by
- 43
- References
- 39
- Citations by year
- 2026: 4 · 2025: 13 · 2024: 10 · 2023: 3 · 2022: 10 · 2021: 3
- FWCI
- 0.71
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- SLAS DISCOVERY (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- 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
- targeted protein degradation, small-molecule degraders, PROTACs, molecular glues, protein unfolding, high-throughput screening, proteasomal degradation, physicochemical properties, drug discovery
- MeSH terms
- Proteostasis, Eukaryotic Cells, Humans, Ligands, Protein Binding, Protein Processing, Post-Translational, Proteomics, Ubiquitin-Protein Ligases, Proteasome Endopeptidase Complex, Small Molecule Libraries, Ubiquitination, Drug Discovery, High-Throughput Screening Assays, Hydrophobic and Hydrophilic Interactions, Protein Unfolding, Molecular Targeted Therapy, Proteolysis
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