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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BindingDB Entry 50014745: Discovery of Highly Potent and Selective IRAK1 Degraders to Probe Scaffolding Functions of IRAK1 in ABC DLBCL.
BindingDB (2023) · UC San Diego · doi:10.7270/q2ms3xmh
BindingDB Entry 50012829: Discovery of First-in-Class Protein Arginine Methyltransferase 5 (PRMT5) Degraders.
BindingDB (2022) · UC San Diego · doi:10.7270/q2765k17
BindingDB Entry 50019525: PROTACS: A technology with a gold rush-like atmosphere.
BindingDB (2024) · UC San Diego · doi:10.7270/q2hq4488
BindingDB Entry 50007767: Small molecule PROTACs in targeted therapy: An emerging strategy to induce protein degradation.
BindingDB (2021) · UC San Diego · doi:10.7270/q2f47sf1
BindingDB Entry 50023756: Discovery and Characterization of RP03707: A Highly Potent and Selective KRASG12D PROTAC.
BindingDB (2026) · UC San Diego · doi:10.7270/q2m90fn6
BindingDB Entry 50007079: Discovery of a First-in-Class Mitogen-Activated Protein Kinase Kinase 1/2 Degrader.
BindingDB (2021) · UC San Diego · doi:10.7270/q23x89xq
BindingDB Entry 50015062: Design and Synthesis of EZH2-Based PROTACs to Degrade the PRC2 Complex for Targeting the Noncatalytic Activity of EZH2.
BindingDB (2023) · UC San Diego · doi:10.7270/q22v2m02
BindingDB Entry 50018757: PROTACs: New method to degrade transcription regulating proteins.
BindingDB (2024) · UC San Diego · doi:10.7270/q2280cvr
BindingDB Entry 50021121: Small-molecule inhibitors targeting apoptosis signal-regulated kinase 1.
BindingDB (2025) · UC San Diego · doi:10.7270/q2sx6jtq
BindingDB Entry 50020587: Small Molecule Inhibitors Targeting the "Undruggable" Survivin: The Past, Present, and Future from a Medicinal Chemist's Perspective.
BindingDB (2024) · UC San Diego · doi:10.7270/q22j6hbq
BindingDB Entry 50007010: Proteolysis Targeting Chimeras for the Selective Degradation of Mcl-1/Bcl-2 Derived from Nonselective Target Binding Ligands.
BindingDB (2021) · UC San Diego · doi:10.7270/q29s1v93
BindingDB Entry 50002351: Mapping the Efficiency and Physicochemical Trajectories of Successful Optimizations.
BindingDB (2020) · UC San Diego · doi:10.7270/q2dj5j62
BindingDB Entry 50011091: Hi-JAK-ing the ubiquitin system: The design and physicochemical optimisation of JAK PROTACs.
BindingDB (2021) · UC San Diego · doi:10.7270/q2h70kd3
BindingDB Entry 50021665: The application of PROTAC in HDAC.
BindingDB (2025) · UC San Diego · doi:10.7270/q2474gjr
BindingDB Entry 50010796: Discovery of Novel PDEδ Degraders for the Treatment of KRAS Mutant Colorectal Cancer.
BindingDB (2021) · UC San Diego · doi:10.7270/q2rn3cfh
BindingDB Entry 50008584: New Modalities, Technologies, and Partnerships in Probe and Lead Generation: Enabling a Mode-of-Action Centric Paradigm.
BindingDB (2021) · UC San Diego · doi:10.7270/q2n301bf
BindingDB Entry 50018446: Revisiting signal transducer and activator of transcription 3 (STAT3) as an anticancer target and its inhibitor discovery: Where are we and where should we go?
BindingDB (2024) · UC San Diego · doi:10.7270/q21j9g13
BindingDB Entry 50018681: A comprehensive review of BET-targeting PROTACs for cancer therapy.
BindingDB (2024) · UC San Diego · doi:10.7270/q2930zdd
BindingDB Entry 50014325: Optimization of a Series of RIPK2 PROTACs.
BindingDB (2022) · UC San Diego · doi:10.7270/q2vd739f
BindingDB Entry 50008493: Design, Synthesis, and Biological Evaluation of MEK PROTACs.
BindingDB (2021) · UC San Diego · doi:10.7270/q2kd229n
BindingDB Entry 50011158: Selective CDK6 degradation mediated by cereblon, VHL, and novel IAP-recruiting PROTACs.
BindingDB (2021) · UC San Diego · doi:10.7270/q2jw8jf1

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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