This study explores the development of a covalent handle based on DCAF16 for the rational design of monovalent molecular glue degraders. The researchers synthesized and screened a series of covalent JQ1 analogs, identifying a vinylsulfonyl piperazine handle that effectively degrades BRD4 in cells. Through chemoproteomic profiling, they identified DCAF16 as the E3 ligase responsible for BRD4 degradation. This handle was then tested on various protein-targeting ligands, demonstrating its ability to induce the degradation of multiple protein targets, including CDK4, SMARCA2/4, and BCR-ABL/c-ABL. The study highlights the potential of covalent handles in expanding the scope of targeted protein degradation applications.This study explores the development of a covalent handle based on DCAF16 for the rational design of monovalent molecular glue degraders. The researchers synthesized and screened a series of covalent JQ1 analogs, identifying a vinylsulfonyl piperazine handle that effectively degrades BRD4 in cells. Through chemoproteomic profiling, they identified DCAF16 as the E3 ligase responsible for BRD4 degradation. This handle was then tested on various protein-targeting ligands, demonstrating its ability to induce the degradation of multiple protein targets, including CDK4, SMARCA2/4, and BCR-ABL/c-ABL. The study highlights the potential of covalent handles in expanding the scope of targeted protein degradation applications.