Integration of Palladium-Catalyzed C-N Coupling into Self-Encoded Libraries for Accelerated Hit Discovery

Abstract

Affinity screenings with encoded libraries are transformative tools for rapid hit discovery from vast compound collections. Yet the adaptation of established chemical reactions to DNA-encoded libraries (DELs) remains challenging due to DNA-compatibility constraints and mismatches between barcode and chemical structure in case of incomplete reactions or side product formation. Recently, we introduced self-encoded libraries (SELs) as a barcode-free alternative to DELs. The SEL platform offers unmatched flexibility in reaction conditions and decodes screening hits directly from their chemical structure, avoiding the problem of mismatched barcode-compound pairs. Here, we expand the SEL platform to Buchwald-Hartwig aminations, enabling the construction of new high diversity SELs. We performed a thorough reaction condition optimization and tested a scope of > 170 different building blocks. We adapted our automated MS/MS-based decoding methodology SIRIUS-COMET to the resulting scaffolds, enabling accurate compound decoding from complex mixtures. A 25,725-member library was synthesized and screened all at once against carbonic anhydrase IX (CAIX), resulting in robust enrichment of hits with specific building block patterns and yielding several nanomolar-affinity binders. This work showcases the seamless integration of palladium-catalyzed cross-couplings into SELs, expanding the chemical space of this technology and accelerating hit discovery with high synthetic versatility.