Development of targeted protein degradation therapeutics

Chamberlain, Philip P.; Hamann, Lawrence G.

doi:10.1038/s41589-019-0362-y

Cited by 489Protein Degradation and InhibitorsChemical Synthesis and AnalysisUbiquitin and proteasome pathways

Development of targeted protein degradation therapeutics

Chamberlain, Philip P., Hamann, Lawrence G.·2019·Nature Chemical Biology

DOI 10.1038/s41589-019-0362-y

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Abstract

Targeted protein degradation as a therapeutic modality has seen dramatic progress and massive investment in recent years because of the convergence of two key scientific breakthroughs: optimization of first-generation peptidic proteolysis-targeted chimeras (PROTACs) into more drug-like molecules able to support in vivo proof of concept and the discovery that clinical molecules function as degraders by binding and repurposing the proteins cereblon and DCAF15. This provided clinical validation for the general approach through the cereblon modulator class of drugs and provided highly drug-like and ligand-efficient E3 ligase binders upon which to tether target-binding moieties. Increasingly rational and systematic approaches including biophysical and structural studies on ternary complexes are being leveraged as the field advances. In this Perspective we summarize the discoveries that have laid the foundation for future degradation therapeutics, focusing on those classes of small molecules that redirect E3 ubiquitin ligases to non-native substrates.

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Molecular glues constitute another important therapeutic class of targeted protein degraders.
“Molecular glues, based on the serendipitous discovery that thalidomide and its analogues act as degrader molecules, constitute another important therapeutic class1–8.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [8]
Elotuzumab has no anti-myeloma activity as monotherapy, but the addition of elotuzumab to lenalidomide or pomalidomide and dexamethasone improved ORRs, PFS and OS in patients with R/R MM.
“The anti-SLAMF7 antibody elotuzumab has no anti-myeloma activity as monotherapy65, but the addition of this agent to lenalidomide or pomalidomide and dexamethasone improved ORRs, PFS and OS in patients with R/R MM47,66,67.”
From Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide (2021) · cites this paper as [65]

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Authors: Chamberlain, P. P., & Hamann, L. G.
Corresponding author: Chamberlain, Philip P.
ORCID: Chamberlain, Philip P.
Hamann, Lawrence G.
Venue: Nature Chemical Biology
Publisher: Springer Science and Business Media LLC
Published: 2019-09-16
Volume: 15
Issue: 10
Pages: 937-944
ISSN: 1552-4450 (ISSN-L)
1552-4469
DOI: 10.1038/s41589-019-0362-y
OpenAlex: W2974568688
Semantic Scholar: 4227e4a70123498985809182272a39c2ba314ab9
Cited by: 489
References: 77
Citations by year: 2026: 50 · 2025: 74 · 2024: 84 · 2023: 74 · 2022: 74 · 2021: 70 · 2020: 62 · 2019: 1
FWCI: 4.70
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Nature Chemical Biology (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
Keywords: targeted protein degradation, PROTACs, DCAF15, protein degraders, ternary complex, ligand efficiency, drug repurposing, small molecule drugs
MeSH terms: Binding Sites, Humans, Protein Binding, Ubiquitin-Protein Ligases, Proteasome Endopeptidase Complex, Small Molecule Libraries, Proteolysis

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