Exploration of the tunability of BRD4 degradation by DCAF16 trans-labelling covalent glues.

ABSTRACT: Chemically induced proximity modalities such as targeted protein degradation (TPD) hold promise for expanding the number of proteins that can be manipulated pharmacologically. However, current TPD strategies are often limited to proteins with preexisting ligands. Molecular glues (e.g. glutarimide ligands for CUL4^CRBN), offer the potential to target undruggable proteins. Yet, their rational design is largely unattainable due to the unpredictability of the 'gain-of-function' nature of the glue interaction upon chemical modification of ligands. We recently reported a covalent trans-labelling glue mechanism which we named 'Template-assisted covalent modification', where an electrophile decorated BRD4 inhibitor was effectively delivered to a cysteine residue on DCAF16 due to an elect

SUBMITTER: Hassan MM 

PROVIDER: S-EPMC11960843 | biostudies-literature | 2024 Dec

REPOSITORIES: biostudies-literature