# Integration of palladium-catalyzed C–N coupling into self-encoded libraries for accelerated hit discovery

## TL;DR

A new method for drug discovery uses self-encoded chemical libraries to quickly find promising compounds with high accuracy.

## Contribution

The integration of palladium-catalyzed C–N coupling into self-encoded libraries expands their chemical diversity and hit discovery potential.

## Key findings

- A 25,725-member library was synthesized and screened against carbonic anhydrase IX, yielding nanomolar-affinity binders.
- Automated MS/MS decoding was adapted to enable accurate compound identification from complex mixtures.
- The platform supports Buchwald–Hartwig aminations with over 170 building blocks tested for scaffold diversity.

## 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.

We expanded the self-encoded library (SEL) platform via C–N cross-couplings, testing 170+ building blocks and generating a 25.725-member library. We established automated MS/MS decoding and demonstrated robust hit enrichment in screens against CAIX.