AutoSPS-D2B: Automated Solid-Phase Synthesis Expands the Reaction Scope for Direct-to-Biology Libraries

Direct-to-biology (D2B) has emerged as a powerful accelerant in early drug discovery, bypassing compound purification to compress the design-make-test-analyse (DMTA) cycle. However, the chemistry underpinning D2B libraries is limited to just a few sequential transformations using assay-compatible reagents and solvents. By contrast, solid-phase synthesis (SPS) empowers a far broader range of reactions and is highly amenable to multistep synthesis, yet its potential as a source for D2B libraries remains largely underexplored. In this study, we develop AutoSPS-D2B, a fully automated solid-phase synthesis workflow that converts multistep, resin-bound chemistry into crude screening libraries that can be assayed directly, expanding reaction scope well beyond the reach of solution-phase D2B. We applied AutoSPS-D2B to explore several distinct chemotypes as allosteric ligands for the immuno-oncology target CCR2. Good agreement was observed in the relative binding affinity trends between crude and pure screening compounds, enabling streamlined ranking of analogues and prioritisation of hits for further investigation. When applied to the advancement of a previously underexplored CCR2 hit, AutoSPS-D2B enabled an analogue space of more than 1,700 building block combinations to be rapidly sampled, leading to optimised compounds with up to six-fold binding affinity improvements in just two DMTA cycles. This work establishes automated SPS as a versatile and efficient engine for D2B-driven hit-to-lead discovery.