Reducing the time and cost of developing PROTAC degraders is a major challenge in the pharmaceutical industry. A PROTAC consists of an E3 ligase ligand (E3-L), a protein of interest ligand (POI-L), and a linker. The efficiency of PROTACs depends on forming a ternary complex with E3 ligase and the POI, and linker optimization plays a critical role in enhancing potency, cooperativity, and physicochemical properties. However, the large size and complex design of PROTACs make optimization time-consuming, especially when relying on cell-based assays. In this study, we applied a Direct-to-Biology (D2B) approach, combining automated chemistry with screening of crude reaction mixtures. This high-throughput method enabled rapid exploration of linker intermediates, providing a time- and cost-effective route to PROTAC optimization