Targeted protein degradation (TPD) describes chemically induced processes leading to the depletion of a target protein (protein of interest, POI) in its cellular environment through coopting of natural intracellular protein degradation mechanisms, such as the ubiquitin-proteasome system (UPS). Over the past decade, TPD has evolved as promising alternative to conventional inhibitor-based therapies, mainly due to the successful development of proteolysis-targeting chimeras (PROTACs). PROTACs are bifunctional molecules consisting of a ligand for a POI and a ligand for an E3 ligase joined by a linker. PROTACs are designed to induce proximity of POI and E3 ligase through formation of a E3:PROTAC:POI ternary complex, thus enabling POI ubiquitination and subsequent proteasomal degradation (Figure ). Diverse approaches have been established to guide and streamline PROTAC development starting from an initial hit compound, including structure-based design and rational design based on structure-activity relationships (SAR) among others. Typically, molecular starting points are identified in direct screens for cellular target degradation of large libraries of previously synthesized PROTACs. Alternative screening approaches rely on cellular target engagement and/or biophysics to evaluate ternary complex formation either with recombinant proteins or in a cellular environment. These initial screening libraries are usually designed by systematically changing E3 ligase and POI ligands, exit vectors for linker attachment on these ligands as well as linker length and nature. Hit identification through these approaches is usually highly time-and resource consuming for both synthesis and biological screening.