Ligand-dependent protein degradation has emerged as a compelling strategy to pharmacologically control the protein content of cells. So far, only a limited number of E3 ligases have been found to support this process. Here, we use a chemical proteomic strategy to discover that DCAF16 -a poorly characterized substrate recognition component of CUL4-DDB1 E3 ubiquitin ligases -promotes nuclear-restricted protein degradation upon modification by cysteine-directed heterobifunctional electrophilic compounds.Conventional small-molecule probes and drugs act by directly perturbing the functions of proteins (e.g., blocking enzyme catalysis or antagonizing receptor signaling). Many proteins, however, possess multiple functional domains, and therefore a compound that binds to only one of these domains may fail to fully inactivate the protein. An alternative emerging strategy uses chemical probes that direct proteins to the proteolytic degradation machinery of the cell, leading to the loss of protein expression 1, 2 . This targeted protein degradation approach leverages two types of small molecules -those that form tripartite complexes with specific E3 ubiquitin ligases and neosubstrate proteins (e.g., the IMiD class of therapeutics 3,4 ) and bifunctional compounds, often referred to as PROTACs (proteolysis targeting chimeras), which couple E3 ligase ligands to substrate ligands via a variably structured linker [5][6][7] . Targeted protein degradation has the potential to act in a catalytic manner 8 that may lower the drug concentrations required to produce a pharmacological effect and operate sub-stoichiometrically to avoid antagonizing the natural functions of the participating E3 ligase. Despite these advantages, to date, only a handful of the 600+ human E3 ligases have been found to support ligand-mediated protein degradation [5][6][7][9][10][11] . Importantly, these E3 ligases has been found to show distinct and restricted substrate specificities 12, 13 , a parameter that is not yet predictable or easily controlled, 3 underscoring the need to discover additional ligandable E3 ligases with differentiated properties to realize the full scope of targeted protein degradation as a pharmacological strategy.We have recently introduced chemical proteomic platforms for globally and sitespecifically mapping the reactivity of electrophilic small molecules in native biological systems [14][15][16] . These experiments have identified a subset of fragment electrophiles, referred to hereafter as 'scouts' 15 , that capture a remarkably broad fraction of the 100s-1000s of covalent small molecule-cysteine interactions discovered so far by chemical proteomics. We surmised herein that these scout fragments, when incorporated into heterotypic bifunctional compounds containing optimized protein ligands, may offer an expedited path to discover E3 ligases capable of supporting targeted protein degradation through covalent reactivity with cysteine residues. With this goal in mind, we fused three scout fragments -KB02, KB03, and KB05 -to the SLF l...