Template-assisted covalent modification underlies activity of covalent molecular glues
Publication information:
Yen-Der Li, Michelle Ma, Muhammad Murtaza Hassan, Moritz Hunkeler, Mingxing Teng, Kedar Puvar, Justine Rutter, Ryan Lumpkin, Brittany Sandoval, Cyrus Jin, Anna Schmoker, Scott Ficarro, Hakyung Cheong, Rebecca Metivier, Michelle Wang, Shawn Xu, Woong Sub Byun, Brian Groendyke, Inchul You, Logan Sigua, Isidoro Tavares, Charles Zou, Jonathan Tsai, Paul Park, Hojong Yoon, Felix Majewski, Haniya Sperling, Jarrod Marto, Jun Qi, Radosław Nowak, Katherine Donovan, Mikołaj Słabicki, Nathanael Gray, Eric Fischer, and Benjamin Ebert. 2024. “Template-Assisted Covalent Modification Underlies Activity of Covalent Molecular Glues”. Nature Chemical Biology
Abstract
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 CUL4DCAF16 ligase to the second bromodomain of BRD4 (BRD4BD2). Through comprehensive biochemical, structural and mutagenesis analyses, we elucidated how pre-existing structural complementarity between DCAF16 and BRD4BD2 serves as a template to optimally orient the degrader for covalent modification of DCAF16Cys58. 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–BRD4BD2 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.