The Advantages of Targeted Protein Degradation Over Inhibition: An RTK Case Study
Open accessAbstract
Proteolysis targeting chimera (PROTAC) technology has emerged over the last two decades as a powerful tool for targeted degradation of endogenous proteins. Herein we describe the development of PROTACs for receptor tyrosine kinases, a protein family yet to be targeted for induced protein degradation. The use of VHL-recruiting PROTACs against this protein family reveals several advantages of degradation over inhibition alone: direct comparisons of fully functional, target-degrading PROTACs with target-inhibiting variants that contain an inactivated E3 ligase-recruiting ligand show that degradation leads to more potent inhibition of cell proliferation and a more durable and sustained downstream signaling response, and thus addresses the kinome rewiring challenge seen with many receptor tyrosine kinase inhibitors. Combined, these findings demonstrate the ability to target receptor tyrosine kinases for degradation using the PROTAC technology and outline the advantages of this degradation-based approach.
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PROTACs can comparatively achieve greater specificity with respect to off-target effects of some kinase inhibitors.
“but given that PROTACs can comparatively achieve greater specificity with respect to off-target effects of some kinase inhibitors126,181”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [181]
PROTACs can be used to overcome drug resistance resulting from mutations of a protein of interest.
“PROTACs can be used to overcome drug resistance resulting from mutations of a POI.”
From PROteolysis TArgeting Chimeras (PROTACs) as emerging anticancer therapeutics (2020) · cites this paper as [4]
PROTACs can have a duration of action that extends beyond clearance and depends on the turnover rate of the protein target rather than residence time.
“and can have a duration of action that extends beyond clearance and depends on the turnover rate of the protein target rather than residence time 23,24,25 .”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [25]
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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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Proteolysis 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-citationRecent Developments in PROTAC‐Mediated Protein Degradation: From Bench to Clinic
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Self-citationEfficient targeted degradation via reversible and irreversible covalent PROTACs
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Antibody Conjugation of a Chimeric BET Degrader Enables <i>in vivo</i> Activity
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<i>In Silico</i> Modeling of PROTAC-Mediated Ternary Complexes: Validation and Application
Drummond, M. L., & Williams, C. I. (2019) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.8b00872 · Cited by 199 · see citing works
PROTACs: A novel strategy for cancer therapy
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Harnessing the Power of Proteolysis for Targeted Protein Inactivation
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Development of the first small molecule histone deacetylase 6 (HDAC6) degraders
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Burslem, G. M., Song, J., Chen, X., Hines, J., & Crews, C. M. (2018) · Journal of the American Chemical Society · doi:10.1021/jacs.8b10320 · Cited by 176 · see citing works
Self-citationDevelopment of Multifunctional Histone Deacetylase 6 Degraders with Potent Antimyeloma Activity
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Rationalizing PROTAC-Mediated Ternary Complex Formation Using Rosetta
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Mutant-selective degradation by BRAF-targeting PROTACs
Alabi, S., Jaime-Figueroa, S., Yao, Z., Gao, Y., Hines, J., Samarasinghe, K. T. G., Vogt, L., Rosen, N., & Crews, C. M. (2021) · Nature Communications · doi:10.1038/s41467-021-21159-7 · Cited by 152 · see citing works
Self-citationA potent KRAS macromolecule degrader specifically targeting tumours with mutant KRAS
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Targeted protein degradation and the enzymology of degraders
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Antibody-mediated delivery of chimeric protein degraders which target estrogen receptor alpha (ERα)
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PROTAC therapy as a new targeted therapy for lung cancer
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Self-citationDevelopment of selective small molecule MDM2 degraders based on nutlin
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Development of covalent inhibitors: Principle, design, and application in cancer
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Self-citationA critical evaluation of the approaches to targeted protein degradation for drug discovery
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Identification and characterization of cancer vulnerabilities via targeted protein degradation
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Targeted protein modification as a paradigm shift in drug discovery
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- Authors
- Burslem, G. M., Smith, B. E., Lai, A. C., Jaime-Figueroa, S., McQuaid, D. C., Bondeson, D. P., Toure, M., Dong, H., Qian, Y., Wang, J., Crew, A. P., Hines, J., & 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
- 67-77.e3
- ISSN
- 2451-9448 (ISSN-L)
- 2451-9456
- PMC
- PMC5831399
- OpenAlex
- W2767251210
- Cited by
- 686
- References
- 64
- Citations by year
- 2026: 84 · 2025: 92 · 2024: 96 · 2023: 83 · 2022: 96 · 2021: 63 · 2020: 89 · 2019: 59 · 2018: 22 · 2017: 1
- FWCI
- 19.31
- 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)
- Research Explorer (The University of Manchester) (submittedVersion, other-oa)
- Funders
- National Institutes of Health
- National Cancer Institute (F99CA212229, R50 CA211252)
- Leukemia and Lymphoma Society
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- PROTACs, targeted protein degradation, receptor tyrosine kinase, VHL E3 ubiquitin ligase, kinase inhibitors, cell proliferation inhibition, downstream signaling
- MeSH terms
- Enzyme Inhibitors, Humans, Ligands, Receptor Protein-Tyrosine Kinases, Ubiquitin-Protein Ligases, Proteolysis
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