Cited by 534Protein Degradation and InhibitorsChemical Synthesis and AnalysisUbiquitin and proteasome pathways

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Protac-Induced Protein Degradation in Drug Discovery: Breaking the Rules or Just Making New Ones?

Churcher, Ian·2018·Journal of Medicinal Chemistry

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Abstract

Targeted protein degradation, using bifunctional small molecules (Protacs) to remove specific proteins from within cells, has emerged as a novel drug discovery strategy with the potential to offer therapeutic interventions not achievable with existing approaches. In this Perspective, the brief history of the field is surveyed from a drug discovery perspective with a focus on the key advances in knowledge which have led to the definition and exemplification of protein degradation concepts and their resulting applications to medicine discovery. The approach has the potential to bring disruptive change to drug discovery; the many potential advantages and outstanding challenges which lie ahead of this technology are discussed.

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Sriram, S., Krishnakumar, P., & Sudandiradoss, C. (2026) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2026.1745654 · Cited by 3
“However, the latest framework of inhibitor action, specifically for PICs (proximity-inducing compounds) like PROTACs uses E3 ligase action to induce targeted protein degradation (Churcher, 2018).”
PROTACs for central nervous system disorders: challenges and opportunities
Zheng, N., Shao, J., Xiong, B., Wei, Y., Wang, X., Zhou, Y., Song, Z., Zhang, A., Xu, C., Zhao, Q., et al. (2026) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2026.118703 · Cited by 4
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“Selectivity, longer-acting activity, and less off-target side effects of this technology in comparison with the traditional inhibition of proteins make it a promising approach to drug discovery (19).”
Background
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“Protein degraders improve upon traditional small molecule inhibition of a protein by exerting prolonged degradation of the targeted proteins and evolution of resistance can be less prominent (Churcher, 2018).”
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Loss of Brd4 alleviates pathological bone loss via Slc9b2 suppression in osteoclastogenesis
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“51 Therefore, dBET6@PSLs were successfully constructed to improve their short half-life in circulation and enhance retention at the disease site.”
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Junker, S., & Clausen, T. (2026) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2025.12.012 · Cited by 2
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The In Vivo Effect of Amorphous Drug Nanoprecipitates on the Intestinal Absorption of the PROTACs ARV-110 (Bavdeglutamide) and ARV-471 (Vepdegestrant)
Niessen, J., Koziolek, M., Indulkar, A. S., Borchardt, T. B., Sjöblom, M., Hedeland, M., Lennernäs, H., & Dahlgren, D. (2026) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.6c00207 · Cited by 3
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Lu, H., Yang, Z., Kayumov, M., Wang, Y., Tang, F., Wang, X., Xia, T., Lei, T., Tong, F., & Gao, H. (2026) · ACS Nano · doi:10.1021/acsnano.6c04420 · Cited by 3
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Webb, D. T., Jones, K. L., Macabuag, N., Bago, R., Betts, J., Bhattacharyya, S., Clifton, S., Tinson, R., Achara, C., Gilbert, S., et al. (2026) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6c00714 · Cited by 2
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Koravović, M., Marković, B. D., Kovačević, M., Rmandić, M., & Tasić, G. (2022) · Journal of the Serbian Chemical Society · doi:10.2298/jsc211209027k · Cited by 2
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“…peptides, millamolecular chemistry (millamolecular chemistry refers to macrocycles with a molecular weight between 500 and 1,000 daltons), PROTACs (Churcher 2017)] to molecular entities grouped under the name “biologics,” such as antibodies, antibody-drug conjugates, peptides, and…”
Background
Specific binding‐induced modulation of the XCL1 metamorphic equilibrium
Dishman, A. F., Peterson, F. C., & Volkman, B. F. (2020) · Biopolymers · doi:10.1002/bip.23402 · Cited by 2
Rôle du facteur de transcription HES6 dans le mélanome uvéal
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Du, W. (2022) · Future Medicinal Chemistry · doi:10.4155/fmc-2022-0147 · Cited by 2
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Kotlarek, D., Pawlik, A., Sagan, M., Sowała, M., Zawiślak-Architek, A., & Walczak, M. (2020) · Technology Transfer and Entrepreneurship · doi:10.2174/2213809907666200130111436 · Cited by 2
Cancer Drug Resistance: Targets and Therapies
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Exploring the Role of PROTACs for the Treatment of Breast Cancer
Pannu, A. S., Goyal, R. K., & Goswami, S. (2024) · Springer eBooks · doi:10.1007/978-981-97-5077-1_12 · Cited by 1

Authors: Churcher, I.
Affiliations: BenevolentBio, 40 Churchway, London NW1 1LW, U.K.
Corresponding author: Churcher, Ian
ORCID: Churcher, Ian
Venue: Journal of Medicinal Chemistry
Publisher: American Chemical Society (ACS)
Published: 2017-12-19
Volume: 61
Issue: 2
Pages: 444-452
ISSN: 0022-2623 (ISSN-L)
1520-4804
DOI: 10.1021/acs.jmedchem.7b01272
OpenAlex: W2769590617
Cited by: 491
References: 67
Citations by year: 2026: 45 · 2025: 61 · 2024: 49 · 2023: 56 · 2022: 53 · 2021: 54 · 2020: 84 · 2019: 64 · 2018: 22 · 2017: 1
FWCI: 4.43
Type: journal article
Language: en
Open access: closed
Locations: Journal of Medicinal Chemistry (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
Physical Sciences › Chemistry › Organic Chemistry › Chemical Synthesis and Analysis
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
Keywords: targeted protein degradation, PROTACs, bifunctional small molecules, protein degradation, drug discovery
MeSH terms: Humans, Peptides, Recombinant Proteins, Drug Design, Ubiquitin-Protein Ligases, Small Molecule Libraries, Ubiquitination, Drug Discovery, Molecular Targeted Therapy, Proteolysis

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Protac-Induced Protein Degradation in Drug Discovery: Breaking the Rules or Just Making New Ones?

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