Expanding the reaction toolbox for nanoscale direct-to-biology PROTAC synthesis and biological evaluation†

Abstract

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_NAr, palladium-mediated cross-coupling and alkylation, in D2B format. Second, the utility of these alternative reactions is demonstrated by rapidly identifying developable PROTACs for a range of protein targets.