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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Possible off-target effects may arise from the E3 ligase ligand side, such as GSPT1 degradation.
“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]
A promiscuous ligand for about 50 kinases could induce only a subset of its targets for degradation when converted into a PROTAC.
“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]
Several mechanisms contribute to increased selectivity of PROTACs, including steric incapability of some targets to form a productive ternary complex, or lack of a suitably positioned lysine residue for ubiquitination.
“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]
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.
“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
The propensity of different E3 ligases to ubiquitinate specific proteins varies.
“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
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 [2]
Addition of a linker with a moiety to recruit either VHL or CRBN reduced foretinib's inhibition for several kinases, but overall both PROTACs retained broad non-selective inhibition.
“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]
A PROTAC's ability to bind the target protein is not the primary determinant of whether efficient degradation occurs; rather, formation of the ternary complex is limiting.
“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]
The extent to which different kinases were degraded was not simply a reflection of how tightly the PROTAC bound the kinase, since inhibition constants were not correlated with cellular degradation.
“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]
Foretinib itself inhibits at least a quarter of the human kinome.
“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]
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.
“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]
PROTAC selectivity does not necessarily mimic that of its target-binding warhead, but rather depends sensitively on the linker.
“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]
PROTACs may benefit from cooperative PPIs between the E3 ligase and the POI, improving potency and selectivity.
“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]
The pairing of VHL versus CRBN for a given target can result in different degradation efficiencies.
“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]
Many PROTACs are not completely selective and can degrade proteins other than their desired targets.
“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]
A major advantage of VHL-based PROTACs is their target-specificity.
“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]
High binary binding affinities are not necessarily needed to result in efficient degradation of a target protein.
“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]
Using the same promiscuous kinase inhibitor as a warhead, the CRBN-based PROTAC degrades more kinases than the VHL-based PROTAC.
“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]
Several PROTACs have been found to be more selective than the inhibitor from which they were derived.
“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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Self-citationA Potent and Selective Small-Molecule Degrader of STAT3 Achieves Complete Tumor Regression In Vivo
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PROTACs: great opportunities for academia and industry
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LYTACs that engage the asialoglycoprotein receptor for targeted protein degradation
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Cellular senescence: a key therapeutic target in aging and diseases
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Plasticity in binding confers selectivity in ligand-induced protein degradation
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Targeted protein degradation: elements of PROTAC design
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Self-citationBAF complex vulnerabilities in cancer demonstrated via structure-based PROTAC design
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PROTACs: An Emerging Therapeutic Modality in Precision Medicine
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Self-citationDifferential PROTAC substrate specificity dictated by orientation of recruited E3 ligase
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Self-citationElectrophilic PROTACs that degrade nuclear proteins by engaging DCAF16
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Development of targeted protein degradation therapeutics
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Targeted protein degradation: from mechanisms to clinic
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Targeted Degradation of Oncogenic KRAS <sup>G12C</sup> by VHL-Recruiting PROTACs
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Self-citationAdvances in Targeting ‘Undruggable’ transcription Factors With Small Molecules
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Delineating the role of cooperativity in the design of potent PROTACs for BTK
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E3 Ligase Ligands for PROTACs: How They Were Found and How to Discover New Ones
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Self-citationSPR-measured dissociation kinetics of PROTAC ternary complexes influence target degradation rate
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Proteolysis-targeting chimeras (PROTACs) in cancer therapy
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Mapping the Degradable Kinome Provides a Resource for Expedited Degrader Development
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Self-citationHIP1R targets PD-L1 to lysosomal degradation to alter T cell–mediated cytotoxicity
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Degradation of proteins by PROTACs and other strategies
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Quantitative Live-Cell Kinetic Degradation and Mechanistic Profiling of PROTAC Mode of Action
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Reversible Spatiotemporal Control of Induced Protein Degradation by Bistable PhotoPROTACs
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Light-induced control of protein destruction by opto-PROTAC
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Target and tissue selectivity of PROTAC degraders
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Self-citationAddressing Kinase-Independent Functions of Fak via PROTAC-Mediated Degradation
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Targeting protein modifications in metabolic diseases: molecular mechanisms and targeted therapies
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Major advances in targeted protein degradation: PROTACs, LYTACs, and MADTACs
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Homolog-Selective Degradation as a Strategy to Probe the Function of CDK6 in AML
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Structure‐Based Design of a Macrocyclic PROTAC
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Unraveling the Role of Linker Design in Proteolysis Targeting Chimeras
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PROteolysis TArgeting Chimeras (PROTACs) as emerging anticancer therapeutics
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Trivalent PROTACs enhance protein degradation via combined avidity and cooperativity
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Self-citationProteolysis Targeting Chimeras (PROTACs) of Anaplastic Lymphoma Kinase (ALK)
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PROTACs: An Emerging Targeting Technique for Protein Degradation in Drug Discovery
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Targeting BCR-ABL1 in Chronic Myeloid Leukemia by PROTAC-Mediated Targeted Protein Degradation
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Self-citationPRosettaC: Rosetta Based Modeling of PROTAC Mediated Ternary Complexes
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Targeted protein degradation for cancer therapy
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Self-citationEfficient targeted degradation via reversible and irreversible covalent PROTACs
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Receptor tyrosine kinases and cancer: oncogenic mechanisms and therapeutic approaches
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Prey for the Proteasome: Targeted Protein Degradation—A Medicinal Chemist's Perspective
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<i>In Silico</i> Modeling of PROTAC-Mediated Ternary Complexes: Validation and Application
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Expanding PROTACtable genome universe of E3 ligases
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Development of the first small molecule histone deacetylase 6 (HDAC6) degraders
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Targeted protein degradation as a powerful research tool in basic biology and drug target discovery
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Physicochemical Property Determinants of Oral Absorption for PROTAC Protein Degraders
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PROTAC-Mediated Degradation of Bruton’s Tyrosine Kinase Is Inhibited by Covalent Binding
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PROTACs: A novel strategy for cancer therapy
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PROTACs to address the challenges facing small molecule inhibitors
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Harnessing the Power of Proteolysis for Targeted Protein Inactivation
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Self-citationPROTAC-mediated degradation reveals a non-catalytic function of AURORA-A kinase
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Self-citationDevelopment of Multifunctional Histone Deacetylase 6 Degraders with Potent Antimyeloma Activity
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INK4 Tumor Suppressor Proteins Mediate Resistance to CDK4/6 Kinase Inhibitors
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How We Think about Targeting RNA with Small Molecules
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Discovery of a first-in-class CDK2 selective degrader for AML differentiation therapy
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Emerging degrader technologies engaging lysosomal pathways
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Homo-PROTACs for the Chemical Knockdown of Cereblon
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Development of a BCL-xL and BCL-2 dual degrader with improved anti-leukemic activity,
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Selective PROTAC-mediated degradation of SMARCA2 is efficacious in SMARCA4 mutant cancers
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Self-citationCereblon versus VHL: Hijacking E3 ligases against each other using PROTACs
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Targeted protein degradation: current and future challenges
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DeepPROTACs is a deep learning-based targeted degradation predictor for PROTACs
Li, F., Hu, Q., Zhang, X., Sun, R., Liu, Z., Wu, S., Tian, S., Ma, X., Dai, Z., Yang, X., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-34807-3 · Cited by 159 · see citing works
Harnessing the E3 Ligase KEAP1 for Targeted Protein Degradation
Wei, J., Meng, F., Park, K.-S., Yim, H., Velez, J., Kumar, P., Wang, L., Xie, L., Chen, H., Shen, Y., et al. (2021) · Journal of the American Chemical Society · doi:10.1021/jacs.1c04841 · Cited by 154 · see citing works
- 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 · 2017: 1 · 2014: 1
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › 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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