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Lessons in PROTAC Design from Selective Degradation with a Promiscuous Warhead
Open accessAbstract
Inhibiting protein function selectively is a major goal of modern drug discovery. Here, we report a previously understudied benefit of small molecule proteolysis-targeting chimeras (PROTACs) that recruit E3 ubiquitin ligases to target proteins for their ubiquitination and subsequent proteasome-mediated degradation. Using promiscuous CRBN- and VHL-recruiting PROTACs that bind >50 kinases, we show that only a subset of bound targets is degraded. The basis of this selectivity relies on protein-protein interactions between the E3 ubiquitin ligase and the target protein, as illustrated by engaged proteins that are not degraded as a result of unstable ternary complexes with PROTAC-recruited E3 ligases. In contrast, weak PROTAC:target protein affinity can be stabilized by high-affinity target:PROTAC:ligase trimer interactions, leading to efficient degradation. This study highlights design guidelines for generating potent PROTACs as well as possibilities for degrading undruggable proteins immune to traditional small-molecule inhibitors.
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In the citing paper
“However, possible off-target effects may arise from the E3 ligase ligand side, such as the degradation of GSPT1 in this work and others[42–44].”
From Development of MDM2 degraders based on ligands derived from Ugi reactions: Lessons and discoveries (2021) · cites this paper as [42]
In the citing paper
“In addition, Bondeson et al. showed that a promiscuous ligand for about 50 kinases could induce only a subset of its targets for degradation when converted into a PROTAC45.”
From Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity (2020) · cites this paper as [45]
In the citing paper
“Several mechanisms have been shown to contribute to this increase in selectivity. This includes steric incapability of some targets to form a productive ternary complex, or lack of a suitably positioned lysine residue for ubiquitination.62−69”
From Advancing Targeted Protein Degradation via Multiomics Profiling and Artificial Intelligence (2023) · cites this paper as [65]
In the citing paper
“Multiple studies have reported that the stability of the E3-degrader-POI ternary complex may influence degradation kinetics and selectivity, and may be a more reliable predictor for degradation than target engagement alone (Bondeson et al., 2018; Roy et al., 2019).”
From Mapping the Degradable Kinome Provides a Resource for Expedited Degrader Development (2020) · cites this paper as Bondeson et al., 2018
In the citing paper
“The propensity of different E3 ligases to ubiquitinate specific proteins has been reported to vary in the literature (Bondeson et al., 2018; Smith et al., 2019) and variation is attributed to the unique protein-protein interactions that may form between the E3 ligase and target.”
From Mapping the Degradable Kinome Provides a Resource for Expedited Degrader Development (2020) · cites this paper as Bondeson et al., 2018
In the citing paper
“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 [2]
In the citing paper
“Addition of a linker with a moiety to recruit either VHL or CRBN reduced foretinib’s inhibition for several of these kinases, but overall both PROTACs retained broad non-selective inhibition.”
From Rationalizing PROTAC-Mediated Ternary Complex Formation Using Rosetta (2021) · cites this paper as [20]
In the citing paper
“It has been shown that a PROTAC’s ability to bind the target protein is not the primary determinant of whether efficient degradation occurs; rather, it has been suggested that formation of the ternary complex is limiting (i.e., the ability of the PROTAC to simultaneously bind both the target protein and the E3 ligase) 20, 22.”
From Rationalizing PROTAC-Mediated Ternary Complex Formation Using Rosetta (2021) · cites this paper as [20]
In the citing paper
“Moreover, the extent to which different kinases were degraded was not simply a reflection related to how tightly the PROTAC bound the kinase, since inhibition constants were not correlated with cellular degradation 20.”
From Rationalizing PROTAC-Mediated Ternary Complex Formation Using Rosetta (2021) · cites this paper as [20]
In the citing paper
“Using a competitive binding assay, foretinib itself was first shown to inhibit at least a quarter of the human kinome 20.”
From Rationalizing PROTAC-Mediated Ternary Complex Formation Using Rosetta (2021) · cites this paper as [20]
In the citing paper
“Remarkably, however, cellular treatment revealed that certain kinases were degraded much more efficiently by the VHL-recruiting PROTAC, while others were degraded more efficiently by the CRBN-recruiting PROTAC 20.”
From Rationalizing PROTAC-Mediated Ternary Complex Formation Using Rosetta (2021) · cites this paper as [20]
In the citing paper
“It has further been shown that PROTAC selectivity does not necessarily mimic that of its target-binding warhead, but rather depends sensitively on the linker 20, 23, 24, 33”
From Rationalizing PROTAC-Mediated Ternary Complex Formation Using Rosetta (2021) · cites this paper as [20]
In the citing paper
“PROTACs may also benefit from cooperative PPIs between the E3 ligase and the POI. This can have the advantages of improved potency49 and selectivity50.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [49]
In the citing paper
“the pairing of VHL versus CRBN for a given target can result in different degradation efficiencies49, as was first observed when targeting the fusion oncogene BCR–ABL by PROTACs118.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [49]
In the citing paper
“In addition, many PROTACs are not completely selective and can degrade proteins other than their desired targets [7, 90, 204, 205].”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [204]
In the citing paper
“A major advantage of VHL-based PROTACs is their target-specificity [44, 53].”
From PROteolysis TArgeting Chimeras (PROTACs) as emerging anticancer therapeutics (2020) · cites this paper as [53]
In the citing paper
“high binary binding affinities are not necessarily needed to result in efficient degradation of a target protein [53]”
From PROteolysis TArgeting Chimeras (PROTACs) as emerging anticancer therapeutics (2020) · cites this paper as [53]
In the citing paper
“using the same promiscuous kinase inhibitor as a warhead, the CRBN-based PROTAC degrades more kinases than the VHL-based PROTAC [53].”
From PROteolysis TArgeting Chimeras (PROTACs) as emerging anticancer therapeutics (2020) · cites this paper as [53]
In the citing paper
“and several PROTACs have been found to be more selective than the inhibitor from which they were derived 12,28,29,30 ,”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [12]
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Metadata
- Authors
- Bondeson, D. P., Smith, B. E., Burslem, G. M., Buhimschi, A. D., Hines, J., Jaime-Figueroa, S., Wang, J., Hamman, B. D., Ishchenko, A., & Crews, C. M.
- Affiliations
- Yale University (US)
- Arvinas (United States) (US)
- Corresponding author
- Crews, Craig M.
- ORCID
- Venue
- Cell Chemical Biology
- Publisher
- Elsevier BV
- Published
- 2018-01
- Volume
- 25
- Issue
- 1
- Pages
- 78-87.e5
- ISSN
- 2451-9448 (ISSN-L)
- 2451-9456
- PMC
- PMC5777153
- OpenAlex
- W2767856718
- Cited by
- 923
- References
- 50
- Citations by year
- 2026: 104 · 2025: 133 · 2024: 147 · 2023: 104 · 2022: 110 · 2021: 110 · 2020: 109 · 2019: 72 · 2018: 29
- FWCI
- 23.80
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell chemical biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NCI (F99 CA212229-02, R50 CA211252-02)
- Leukemia and Lymphoma Society Career Development
- 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
- Physical Sciences › Chemistry › Organic Chemistry › Chemical Synthesis and Analysis
- Keywords
- PROTACs, protein degradation, E3 ubiquitin ligase, cereblon, VHL, protein-protein interaction, ternary complex stability, PROTAC design, undruggable proteins, ubiquitination, proteasome
- MeSH terms
- Humans, Drug Design, Ubiquitin-Protein Ligases, Proteasome Endopeptidase Complex, Protein Kinase Inhibitors, Small Molecule Libraries, Ubiquitination, Proteolysis
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