Template-assisted covalent modification underlies activity of covalent molecular glues

Molecular glues are proximity-inducing small molecules that have emerged as an attractive therapeutic approach. However, developing molecular glues remains challenging, requiring innovative mechanistic strategies to stabilize neoprotein interfaces and expedite discovery. Here we unveil a trans -labe...

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Vydané v:	Nature chemical biology Ročník 20; číslo 12; s. 1640 - 1649
Hlavní autori:	Li, Yen-Der, Ma, Michelle W., Hassan, Muhammad Murtaza, Hunkeler, Moritz, Teng, Mingxing, Puvar, Kedar, Rutter, Justine C., Lumpkin, Ryan J., Sandoval, Brittany, Jin, Cyrus Y., Schmoker, Anna M., Ficarro, Scott B., Cheong, Hakyung, Metivier, Rebecca J., Wang, Michelle Y., Xu, Shawn, Byun, Woong Sub, Groendyke, Brian J., You, Inchul, Sigua, Logan H., Tavares, Isidoro, Zou, Charles, Tsai, Jonathan M., Park, Paul M. C., Yoon, Hojong, Majewski, Felix C., Sperling, Haniya T., Marto, Jarrod A., Qi, Jun, Nowak, Radosław P., Donovan, Katherine A., Słabicki, Mikołaj, Gray, Nathanael S., Fischer, Eric S., Ebert, Benjamin L.
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	New York Nature Publishing Group US 01.12.2024 Nature Publishing Group
Predmet:	631/154/309 631/45/535 631/92/609 631/92/613 Adhesives Biochemical Engineering Biochemistry Bioorganic Chemistry Bromodomain Containing Proteins Cell Biology Cell Cycle Proteins - chemistry Cell Cycle Proteins - metabolism Chemistry Chemistry and Materials Science Chemistry/Food Science Complementarity Covalence Glues HEK293 Cells Humans Labeling Medical innovations Models, Molecular Mutagenesis Pharmacology Protein Binding Proteolysis Transcription Factors - chemistry Transcription Factors - metabolism
ISSN:	1552-4450, 1552-4469, 1552-4469
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Popis
Shrnutí:	Molecular glues are proximity-inducing small molecules that have emerged as an attractive therapeutic approach. However, developing molecular glues remains challenging, requiring innovative mechanistic strategies to stabilize neoprotein interfaces and expedite discovery. Here we unveil a trans -labeling covalent molecular glue mechanism, termed ‘template-assisted covalent modification’. We identified a new series of BRD4 molecular glue degraders that recruit CUL4 DCAF16 ligase to the second bromodomain of BRD4 (BRD4 BD2 ). Through comprehensive biochemical, structural and mutagenesis analyses, we elucidated how pre-existing structural complementarity between DCAF16 and BRD4 BD2 serves as a template to optimally orient the degrader for covalent modification of DCAF16 Cys58 . This process stabilizes the formation of BRD4–degrader–DCAF16 ternary complex and facilitates BRD4 degradation. Supporting generalizability, we found that a subset of degraders also induces GAK–BRD4 BD2 interaction through trans -labeling of GAK. Together, our work establishes ‘template-assisted covalent modification’ as a mechanism for covalent molecular glues, which opens a new path to proximity-driven pharmacology. Characterization of DCAF16-based BRD4 molecular glue degraders revealed a trans -labeling mechanism termed ‘template-assisted covalent modification’, which opens a new path for proximity-driven pharmacology.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	1552-4450 1552-4469 1552-4469
DOI:	10.1038/s41589-024-01668-4