biostudies-literatureUnknown16(3)Stevens RRoyal Commission for the Exhibition of 1851GlaxoSmithKlineSociety of Chemical IndustryUniversity of StrathclydeHigh-throughput chemistry (HTC) and direct-to-biology (D2B) platforms allow for plate-based compound synthesis and biological evaluation of crude mixtures in cellular assays. The rise of these workflows has rapidly accelerated drug-discovery programs in the field of targeted protein degradation (TPD) in recent years by removing a key bottleneck of compound purification. However, the number of chemical transformations amenable to this methodology remain minimal, leading to limitations in the exploration of chemical space using existing library-based approaches. In this work, we expanded the toolbox by synthesising a library of degraders in D2B format. First, reaction conditions are established for performing key medicinal chemistry transformations, including reductive amination, S<sub>N</suRSC medicinal chemistry1141-1150https://www.ebi.ac.uk/biostudies/studies/S-EPMC11664481biostudies-literatureExpanding the reaction toolbox for nanoscale direct-to-biology PROTAC synthesis and biological evaluation.PMC11664481Cryan JKlimaszewska DStevens RMiah AHShrives HJStacey PHarling JDBattersby DJBurley GAfalseExpanding the reaction toolbox for nanoscale direct-to-biology PROTAC synthesis and biological evaluation.High-throughput chemistry (HTC) and direct-to-biology (D2B) platforms allow for plate-based compound synthesis and biological evaluation of crude mixtures in cellular assays. The rise of these workflows has rapidly accelerated drug-discovery programs in the field of targeted protein degradation (TPD) in recent years by removing a key bottleneck of compound purification. However, the number of chemical transformations amenable to this methodology remain minimal, leading to limitations in the exploration of chemical space using existing library-based approaches. In this work, we expanded the toolbox by synthesising a library of degraders in D2B format. First, reaction conditions are established for performing key medicinal chemistry transformations, including reductive amination, S<sub>N</su2025-01-01T00:00:00Z2025 Mar2026-06-08T05:13:18.712Z2025-04-04T02:54:31.362ZS-EPMC116644813972074010.1039/d4md00760c