This study introduces a DCAF16-based covalent handle that enables the rational design of monovalent degraders for various protein targets. The covalent handle, vinylsulfonyl piperazine, was tested with the BET family inhibitor JQ1 and successfully induced the degradation of BRD4 in cells. Through chemoproteomic profiling, DCAF16 was identified as the E3 ligase responsible for BRD4 degradation. The handle was then transplanted onto other protein-targeting ligands, leading to the degradation of CDK4, the androgen receptor, BTK, SMARCA2/4, and BCR-ABL/c-ABL. The study demonstrates that this covalent handle can be used to degrade multiple protein classes without the need for a linker. The results suggest that DCAF16 is a promising target for covalent targeting in targeted protein degradation applications. However, the potency, selectivity, and pharmacokinetic properties of the covalent handle need further improvement for future translational efforts. The study also highlights the potential of DCAF16 in enabling the degradation of various neo-substrate proteins compared to other E3 ligases. The findings provide a new approach for the rational design of covalent degraders and expand the scope of targeted protein degradation applications.This study introduces a DCAF16-based covalent handle that enables the rational design of monovalent degraders for various protein targets. The covalent handle, vinylsulfonyl piperazine, was tested with the BET family inhibitor JQ1 and successfully induced the degradation of BRD4 in cells. Through chemoproteomic profiling, DCAF16 was identified as the E3 ligase responsible for BRD4 degradation. The handle was then transplanted onto other protein-targeting ligands, leading to the degradation of CDK4, the androgen receptor, BTK, SMARCA2/4, and BCR-ABL/c-ABL. The study demonstrates that this covalent handle can be used to degrade multiple protein classes without the need for a linker. The results suggest that DCAF16 is a promising target for covalent targeting in targeted protein degradation applications. However, the potency, selectivity, and pharmacokinetic properties of the covalent handle need further improvement for future translational efforts. The study also highlights the potential of DCAF16 in enabling the degradation of various neo-substrate proteins compared to other E3 ligases. The findings provide a new approach for the rational design of covalent degraders and expand the scope of targeted protein degradation applications.