Targeted protein degradation by PROTACs
Abstract
Targeted protein degradation using the PROTAC technology is emerging as a novel therapeutic method to address diseases driven by the aberrant expression of a disease-causing protein. PROTAC molecules are bifunctional small molecules that simultaneously bind a target protein and an E3-ubiquitin ligase, thus causing ubiquitination and degradation of the target protein by the proteasome. Like small molecules, PROTAC molecules possess good tissue distribution and the ability to target intracellular proteins. Herein, we highlight the advantages of protein degradation using PROTACs, and provide specific examples where degradation offers therapeutic benefit over classical enzyme inhibition. Foremost, PROTACs can degrade proteins regardless of their function. This includes the currently "undruggable" proteome, which comprises approximately 85% of all human proteins. Other beneficial aspects of protein degradation include the ability to target overexpressed and mutated proteins, as well as the potential to demonstrate prolonged pharmacodynamics effect beyond drug exposure. Lastly, due to their catalytic nature and the pre-requisite ubiquitination step, an exquisitely potent molecules with a high degree of degradation selectivity can be designed. Impressive preclinical in vitro and in vivo PROTAC data have been published, and these data have propelled the development of clinically viable PROTACs. With the molecular weight falling in the 700-1000Da range, the delivery and bioavailability of PROTACs remain the largest hurdles on the way to the clinic. Solving these issues and demonstrating proof of concept clinical data will be the focus of many labs over the next few years.
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PROTACs act catalytically to induce protein degradation in a sub-stoichiometric manner and their effect is not limited by equilibrium occupancy.
“This is because PROTACs act catalytically to induce protein degradation in a sub-stoichiometric manner and their effect is not limited by equilibrium occupancy32,39.”
From Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity (2020) · cites this paper as [32]
PROTACs usually have a longer-lasting effect and require less systemic drug exposure to be effective than their corresponding payloads.
“These results are in agreement with the unique mechanism of action of PROTACs, that usually have a longer-lasting effect and require less systemic drug exposure to be effective than their corresponding “payloads”.”
From Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity (2020) · cites this paper as [32]
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Wang, K., Dai, X., Yu, A., Feng, C., Liu, K., & Huang, L. (2022) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-022-02483-2 · Cited by 115 · see citing works
Antibody-mediated delivery of chimeric protein degraders which target estrogen receptor alpha (ERα)
Dragovich, P. S., Adhikari, P., Blake, R. A., Blaquiere, N., Chen, J., Cheng, Y.-X., den Besten, W., Han, J., Hartman, S. J., He, J., et al. (2020) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2019.126907 · Cited by 120 · see citing works
Plasticity in designing PROTACs for selective and potent degradation of HDAC6
Yang, H., Lv, W., He, M., Deng, H., Li, H., Wu, W., & Rao, Y. (2019) · Chemical Communications · doi:10.1039/c9cc08509b · Cited by 108 · see citing works
De Dominici, M., Porazzi, P., Xiao, Y., Chao, A., Tang, H.-Y., Kumar, G., Fortina, P., Spinelli, O., Rambaldi, A., Peterson, L. F., et al. (2020) · Blood · doi:10.1182/blood.2019003604 · Cited by 94 · see citing works
UBE2G1 governs the destruction of cereblon neomorphic substrates
Lu, G., Weng, S., Matyskiela, M., Zheng, X., Fang, W., Wood, S., Surka, C., Mizukoshi, R., Lu, C.-C., Mendy, D., et al. (2018) · eLife · doi:10.7554/elife.40958 · Cited by 78 · see citing works
Novel PROTACs for degradation of SHP2 protein
Zheng, M., Liu, Y., Wu, C., Yang, K., Wang, Q., Zhou, Y., Chen, L., & Li, H. (2021) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2021.104788 · Cited by 81 · see citing works
Bai, N., Riching, K. M., Makaju, A., Wu, H., Acker, T. M., Ou, S.-C., Zhang, Y., Shen, X., Bulloch, D. N., Rui, H., et al. (2022) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.101653 · Cited by 77 · see citing works
PIKES Analysis Reveals Response to Degraders and Key Regulatory Mechanisms of the CRL4 Network
Reichermeier, K. M., Straube, R., Reitsma, J. M., Sweredoski, M. J., Rose, C. M., Moradian, A., den Besten, W., Hinkle, T., Verschueren, E., Petzold, G., et al. (2020) · Molecular Cell · doi:10.1016/j.molcel.2019.12.013 · Cited by 78 · see citing works
Selective CDK6 degradation mediated by cereblon, VHL, and novel IAP-recruiting PROTACs
Anderson, N. A., Cryan, J., Ahmed, A., Dai, H., McGonagle, G. A., Rozier, C., & Benowitz, A. B. (2020) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2020.127106 · Cited by 69 · see citing works
Monomeric Targeted Protein Degraders
Hanan, E. J., Liang, J., Wang, X., Blake, R. A., Blaquiere, N., & Staben, S. T. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c00093 · Cited by 69 · see citing works
A critical evaluation of the approaches to targeted protein degradation for drug discovery
Chopra, R., Sadok, A., & Collins, I. (2019) · Drug Discovery Today: Technologies · doi:10.1016/j.ddtec.2019.02.002 · Cited by 53 · see citing works
Scrutinizing the Therapeutic Potential of PROTACs in the Management of Alzheimer’s Disease
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From serendipity to strategy: molecular glue degraders in cancer therapeutics
Darling, S., Bajrami, I., & West, S. C. (2025) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.1080/10409238.2025.2564068 · Cited by 10 · see citing works
“%) of proteins arising from disease-causing genes are considered “undruggable” (Neklesa et al. 2017) (Figure 1A). their low tractability often stems from small or featureless functional interfaces; the lack of defined hydrophobic pockets is detri-mentally challenging for ligand binding (Figure 1B,…”
Exploiting the intrinsic misfolding propensity of the KRAS oncoprotein
Janssen, K., Claes, F., Van de Velde, D., Wehbi, V. L., Houben, B., Lampi, Y., Nys, M., Khodaparast, L., Khodaparast, L., Louros, N., et al. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2214921120 · Cited by 10 · see citing works
- Authors
- Neklesa, T. K., Winkler, J. D., & Crews, C. M.
- Affiliations
- Arvinas (United States) (US)
- Yale University (US)
- Corresponding author
- Neklesa, Taavi K.
- Venue
- Pharmacology & Therapeutics
- Publisher
- Elsevier BV
- Published
- 2017-06
- Volume
- 174
- Pages
- 138-144
- ISSN
- 0163-7258 (ISSN-L)
- OpenAlex
- W2589026097
- Cited by
- 599
- References
- 50
- Citations by year
- 2026: 61 · 2025: 103 · 2024: 85 · 2023: 66 · 2022: 67 · 2021: 56 · 2020: 60 · 2019: 53 · 2018: 35 · 2017: 13
- FWCI
- 4.20
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Pharmacology & Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (R44CA203199)
- 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, targeted protein degradation, bifunctional small molecules, E3 ubiquitin ligase, ubiquitination, proteasome, undruggable proteins, protein overexpression, pharmacodynamics, bioavailability, drug delivery
- MeSH terms
- Enzyme Inhibitors, Humans, Molecular Weight, Proteins, Drug Design, Drug Delivery Systems, Proteasome Endopeptidase Complex, Ubiquitination, Molecular Targeted Therapy, Proteolysis
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