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Cited by 35Protein Degradation and InhibitorsUbiquitin and proteasome pathwaysChemical Synthesis and Analysis

Selective Wee1 degradation by PROTAC degraders recruiting VHL and CRBN E3 ubiquitin ligases

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Aublette, Marine C., Harrison, Tom A., Thorpe, Elizabeth J., Gadd, Morgan S.·2022·Bioorganic & Medicinal Chemistry Letters
DOI 10.1016/j.bmcl.2022.128636
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Abstract

/M checkpoint by phosphorylating CDK1 when DNA is damaged to allow time for DNA to repair, disruption of which is a key approach to sensitise cancer cells to DNA-damaging therapies. The main selective inhibitor for Wee1 undergoing development in clinical trials, AZD1775, however, has been shown to have off target effects towards other protein kinases with similar potency. Here we describe the synthesis and assessment of a series of Wee1-degrading PROTACs using AZD1775 linked to either the VHL ligand VH032 or to the CRBN ligand pomalidomide using different types and lengths of linkers. The conversion of AZD1775 into a PROTAC induces selective Wee1 degradation for compounds of both series depending on the nature of the linker.

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  • Modification of the E3 ligands prevents the recruitment of their respective E3 ligases by the PROTAC, allowing assessment of PROTAC activity in the absence of the E3 ligase.

    “The modification of the E3 ligands prevents the recruitment of their respective E3 ligases by the PROTAC, thereby allowing the assessment of the activity of the PROTAC in the absence of the E3 ligase45,46.”

    From An HDAC4-specific PROTAC degrader achieves radiation sensitization by enhancing ferroptosis in lung cancer (2026) · cites this paper as [46]

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Cited by

Sorted by citations

Authors
Aublette, M. C., Harrison, T. A., Thorpe, E. J., & Gadd, M. S.
Affiliations
Lancaster University (GB)
Corresponding author
Gadd, Morgan S.
ORCID
Venue
Bioorganic & Medicinal Chemistry Letters
Publisher
Elsevier BV
Published
2022-05
Volume
64
Pages
128636
ISSN
0960-894X (ISSN-L)
DOI
10.1016/j.bmcl.2022.128636
OpenAlex
W4214586577
Cited by
35
References
5
Citations by year
2026: 7 · 2025: 11 · 2024: 8 · 2023: 6 · 2022: 3
FWCI
2.29
Type
journal article
Language
en
Open access
Licence
Locations
  • Bioorganic & Medicinal Chemistry Letters (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Lancaster EPrints (Lancaster University) (submittedVersion)
Funders
North West Cancer Research (LFSL2018-23)
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
WEE1, PROTAC degraders, VHL E3 ubiquitin ligase, AZD1775, pomalidomide, linker length, selective protein degradation, CDK1 phosphorylation, DNA damage response, off-target kinase inhibition
MeSH terms
DNA Damage, DNA Repair, Ligands, Protein-Tyrosine Kinases, Pyrazoles, Pyrimidinones, Cell Cycle Proteins, Ubiquitin-Protein Ligases, Proteolysis

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