Discovery of CRBN-Dependent WEE1 Molecular Glue Degraders from a Multicomponent Combinatorial Library

Small molecules promoting protein-protein interactions produce a range of therapeutic outcomes. Molecular glue degraders exemplify this concept due to their compact drug-like structures and ability to engage targets without reliance on existing cognate ligands. While cereblon molecular glue degrader...

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Published in:Journal of the American Chemical Society Vol. 146; no. 46; pp. 31433 - 31443
Main Authors: Razumkov, Hlib, Jiang, Zixuan, Baek, Kheewoong, You, Inchul, Geng, Qixiang, Donovan, Katherine A., Tang, Michelle T., Metivier, Rebecca J., Mageed, Nada, Seo, Pooreum, Li, Zhengnian, Byun, Woong Sub, Hinshaw, Stephen M., Sarott, Roman C., Fischer, Eric S., Gray, Nathanael S.
Format: Journal Article
Language:English
Published: WASHINGTON Amer Chemical Soc 20.11.2024
Subjects:
Adaptor Proteins, Signal Transducing - chemistry
Adaptor Proteins, Signal Transducing - metabolism
Cell Cycle Proteins - chemistry
Cell Cycle Proteins - metabolism
Chemistry
Chemistry, Multidisciplinary
Combinatorial Chemistry Techniques
Drug Discovery
Humans
Models, Molecular
Molecular Structure
Physical Sciences
Protein-Tyrosine Kinases - antagonists & inhibitors
Protein-Tyrosine Kinases - chemistry
Protein-Tyrosine Kinases - metabolism
Science & Technology
Small Molecule Libraries - chemical synthesis
Small Molecule Libraries - chemistry
Small Molecule Libraries - pharmacology
Ubiquitin-Protein Ligases
DEGRADATION
INHIBITION
KINASE
LIGASE
ISSN:0002-7863, 1520-5126, 1520-5126
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Summary:Small molecules promoting protein-protein interactions produce a range of therapeutic outcomes. Molecular glue degraders exemplify this concept due to their compact drug-like structures and ability to engage targets without reliance on existing cognate ligands. While cereblon molecular glue degraders containing glutarimide scaffolds have been approved for treatment of multiple myeloma and acute myeloid leukemia, the design of new therapeutically relevant monovalent degraders remains challenging. We report here an approach to glutarimide-containing molecular glue synthesis using multicomponent reactions as a central modular core-forming step. Screening the resulting library identified HRZ-1 derivatives that target casein kinase 1 alpha (CK1 alpha) and Wee-like protein kinase (WEE1). Further medicinal chemistry efforts led to identification of selective monovalent WEE1 degraders that provide a potential starting point for the eventual development of a selective chemical degrader probe. The structure of the hit WEE1 degrader complex with CRBN-DDB1 and WEE1 provides a model of the protein-protein interface and ideas to rationalize the observed kinase selectivity. Our findings suggest that modular synthetic routes combined with in-depth structural characterization give access to selective molecular glue degraders and expansion of the CRBN-degradable proteome.
Bibliography:Swiss National Science Foundation (SNF)
ObjectType-Article-1
SourceType-Scholarly Journals-1
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content type line 23
ISSN:0002-7863
1520-5126
1520-5126
DOI:10.1021/jacs.4c06127