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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Background
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PROTACs: New method to degrade transcription regulating proteins
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Inducing Protein Degradation as a Therapeutic Strategy
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PROTACS: A technology with a gold rush-like atmosphere
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PROTAC-Induced Glycogen Synthase Kinase 3β Degradation as a Potential Therapeutic Strategy for Alzheimer’s Disease
Guardigni, M., Pruccoli, L., Santini, A., Simone, A. D., Bersani, M., Spyrakis, F., Frabetti, F., Uliassi, E., Andrisano, V., Pagliarani, B., et al. (2023) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.3c00096 · Cited by 43
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Orally Bioavailable Proteolysis-Targeting Chimeras: An Innovative Approach in the Golden Era of Discovering Small-Molecule Cancer Drugs
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Free Ligand 1D NMR Conformational Signatures To Enhance Structure Based Drug Design of a Mcl-1 Inhibitor (AZD5991) and Other Synthetic Macrocycles
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Traceless Staudinger ligation enabled parallel synthesis of proteolysis targeting chimera linker variants
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“PROTACs use two binding sites to attach to a target protein and recruit an E3 ubiquitin ligase, triggering the degradation of the protein in question [153, 154].”
Background
ByeTAC: Bypassing E-Ligase-Targeting Chimeras for Direct Proteasome Degradation
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Light-Controllable PROTACs for Temporospatial Control of Protein Degradation
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“By hijacking the endogenous UPS to specifically degrade proteins of interest (POI), PROTACs are theoretically capable of targeting any proteins in cells (Sakamoto, 2010; Neklesa et al., 2017; Churcher, 2018; Guo et al., 2019; Paiva and Crews, 2019).”
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Inducing Protein Degradation as a Therapeutic Strategy
Crews, C. M., Georg, G. I., & Wang, S. (2016) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b00735 · Cited by 38
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Background
Preclinical evaluation of proteolytic targeting of LCK as a therapeutic approach in T cell acute lymphoblastic leukemia
Hu, J., Jarusiewicz, J., Du, G., Nishiguchi, G., Yoshimura, S., Panetta, J. C., Li, Z., Min, J., Yang, L., Chepyala, D., et al. (2022) · Science Translational Medicine · doi:10.1126/scitranslmed.abo5228 · Cited by 35
A comprehensive review of BET-targeting PROTACs for cancer therapy
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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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