Differential PROTAC substrate specificity dictated by orientation of recruited E3 ligase
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PROteolysis-TArgeting Chimeras (PROTACs) are hetero-bifunctional molecules that recruit an E3 ubiquitin ligase to a given substrate protein resulting in its targeted degradation. Many potent PROTACs with specificity for dissimilar targets have been developed; however, the factors governing degradation selectivity within closely-related protein families remain elusive. Here, we generate isoform-selective PROTACs for the p38 MAPK family using a single warhead (foretinib) and recruited E3 ligase (von Hippel-Lindau). Based on their distinct linker attachments and lengths, these two PROTACs differentially recruit VHL, resulting in degradation of p38α or p38δ. We characterize the role of ternary complex formation in driving selectivity, showing that it is necessary, but insufficient, for PROTAC-induced substrate ubiquitination. Lastly, we explore the p38δ:PROTAC:VHL complex to explain the different selectivity profiles of these PROTACs. Our work attributes the selective degradation of two closely-related proteins using the same warhead and E3 ligase to heretofore underappreciated aspects of the ternary complex model.
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Several mechanisms contribute to increased selectivity of PROTACs, including steric incapability of some targets to form a productive ternary complex, or lack of a suitably positioned lysine residue for ubiquitination.
“Several mechanisms have been shown to contribute to this increase in selectivity. This includes steric incapability of some targets to form a productive ternary complex, or lack of a suitably positioned lysine residue for ubiquitination.62−69”
From Advancing Targeted Protein Degradation via Multiomics Profiling and Artificial Intelligence (2023) · cites this paper as [68]
The propensity of different E3 ligases to ubiquitinate specific proteins varies.
“The propensity of different E3 ligases to ubiquitinate specific proteins has been reported to vary in the literature (Bondeson et al., 2018; Smith et al., 2019) and variation is attributed to the unique protein-protein interactions that may form between the E3 ligase and target.”
From Mapping the Degradable Kinome Provides a Resource for Expedited Degrader Development (2020) · cites this paper as Smith et al., 2019
AR, ER, FAK, P38 PROTACs have been developed against different solid tumors.
“For example, PROTACs against BRD4, BTK, BCR-ABL and CDK-6 etc. have shown efficacy in leukemia [22, 44, 58, 60], whereas AR, ER, FAK, P38 PROTACs have been developed against different solid tumors [13, 49, 51, 104] (Table 1).”
From PROteolysis TArgeting Chimeras (PROTACs) as emerging anticancer therapeutics (2020) · cites this paper as [51]
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Discovery of a Novel BCL-X<sub>L</sub> PROTAC Degrader with Enhanced BCL-2 Inhibition
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- Authors
- Smith, B. E., Wang, S. L., Jaime-Figueroa, S., Harbin, A., Wang, J., Hamman, B. D., & Crews, C. M.
- Affiliations
- Yale University (US)
- Arvinas (United States) (US)
- Corresponding author
- Crews, Craig M.
- Venue
- Nature Communications
- Published
- 2019-01-10
- Volume
- 10
- Issue
- 1
- Pages
- 131-131
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC6328587
- OpenAlex
- W2909353434
- Cited by
- 517
- References
- 72
- Citations by year
- 2026: 50 · 2025: 74 · 2024: 81 · 2023: 61 · 2022: 75 · 2021: 68 · 2020: 73 · 2019: 34
- FWCI
- 21.25
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health
- National Cancer Institute (R35CA197589)
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Keywords
- PROTACs, targeted protein degradation, VHL, p38 MAPK, p38α, p38δ, linker length, ternary complex model, ubiquitination, foretinib, warheads
- MeSH terms
- Protein Domains, Humans, Models, Molecular, Substrate Specificity, Molecular Structure, Ubiquitin-Protein Ligases, p38 Mitogen-Activated Protein Kinases, Von Hippel-Lindau Tumor Suppressor Protein, Small Molecule Libraries, Ubiquitination, Proteolysis
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