Cited by 173Protein Degradation and InhibitorsUbiquitin and proteasome pathwaysChemical Synthesis and Analysis

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Haven't got a glue: Protein surface variation for the design of molecular glue degraders

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Kozicka, Zuzanna, Thomä, Nicolas Holger·2021·Cell Chemical Biology

DOI 10.1016/j.chembiol.2021.04.009

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Abstract

Molecular glue degraders are small, drug-like compounds that induce interactions between an E3 ubiquitin ligase and a target, which result in ubiquitination and subsequent degradation of the recruited protein. In recent years, serendipitous discoveries revealed that some preclinical and clinical compounds already work as molecular glue degraders, with many more postulated to destabilize their targets through indirect or yet unresolved mechanisms. Here we review strategies by which E3 ubiquitin ligases can be reprogrammed by monovalent degraders, with a focus on molecular glues hijacking cullin-RING ubiquitin ligases. We argue that such drugs exploit the intrinsic property of proteins to form higher-order assemblies, a phenomenon previously seen with disease-causing sequence variations. Modifications of the protein surface by a bound small molecule can change the interactome of the target protein. By inducing interactions between a ligase and a substrate, molecular glue degraders offer an exciting path for the development of novel therapeutics.

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Authors: Kozicka, Z., & Thomä, N. H.
Affiliations: University of Basel (CH)
Friedrich Miescher Institute (CH)
Corresponding author: Thomä, Nicolas Holger
ORCID: Kozicka, Zuzanna
Thomä, Nicolas Holger
Venue: Cell Chemical Biology
Publisher: Elsevier BV
Published: 2021-07
Volume: 28
Issue: 7
Pages: 1032-1047
ISSN: 2451-9448 (ISSN-L)
2451-9456
DOI: 10.1016/j.chembiol.2021.04.009
OpenAlex: W3158527646
Semantic Scholar: ae8a5b956b209af205f68e27236708f9dc194e10
Cited by: 170
References: 111
Citations by year: 2026: 37 · 2025: 40 · 2024: 28 · 2023: 34 · 2022: 29 · 2021: 2
FWCI: 2.52
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 379 d)
doi.org/10.15223/policy-017 (stm-asf)
doi.org/10.15223/policy-037 (stm-asf)
doi.org/10.15223/policy-012 (stm-asf)
doi.org/10.15223/policy-029 (stm-asf)
doi.org/10.15223/policy-004 (stm-asf)
Locations: Cell chemical biology (publishedVersion)
PubMed (publishedVersion)
Zenodo (CERN European Organization for Nuclear Research) (submittedVersion)
Funders: European Research Council (666068)
European Commission (765445)
Horizon 2020
Novartis Foundation
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (186230, KFS-4980-02-2020)
Oncosuisse
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
Physical Sciences › Chemistry › Organic Chemistry › Chemical Synthesis and Analysis
Keywords: molecular glues, E3 ubiquitin ligase, cullin-RING ubiquitin ligases, protein degradation, protein surface modification, protein-protein interaction, protein assembly, drug design, protein-protein interaction network
MeSH terms: Enzyme Inhibitors, Humans, Ubiquitin-Protein Ligases, Small Molecule Libraries, Ubiquitination

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Haven't got a glue: Protein surface variation for the design of molecular glue degraders

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