Discovery of small molecules that interact with biological targets of interest constitutes a fundamental initial step in pharmacological research. Advances in target identification and disease characterization continuously expand the scope of relevant targets into uncharted territory. The efficient identification of ligands for these targets necessitates the rapid exploration and expansion of known or underexplored chemical space. Overcoming the bottleneck of classical high-throughput screens, encoded library technologies featuring chemical diversity on a massive scale have enabled affinity-based hit identification from billions of compounds in a single selection experiment. Most prominently, DNA-encoded libraries (DELs) have found widespread success in academic and industrial research programs. Nonetheless, DELs suffer from several limitations, including suitable chemical reaction conditions during synthesis, challenges in the evaluation of DNA- and RNA-binding targets, and possible binding interference as a result of the sterically demanding encoding tag. These disadvantages limit the range of possible chemical space which can be explored, both in regard to the small molecule as well as the target.<br/>We report our on-going efforts in the development of a next-generation combinatorial library platform which leverages a novel encoding strategy featuring a small and chemically inert encoding tag suitable for affinity screening of a wide range of targets, including targets that interact with nucleic acids. The library system consists of small molecule and encoding tag hybrid constructs, which are efficiently prepared, enriched, and sequenced owing to an optimized synthetic strategy combining orthogonal protecting groups and cleavable linkers. The excellent chemical inertness of the encoding tags allows for the implementation of a wide range of reaction conditions in order to expand the chemical space beyond current state-of-the-art encoded libraries. Accordingly, we have successfully implemented powerful Pd-mediated cross coupling reactions which allow access to core structures of high biological and therapeutic relevance. While still in early stages, we anticipate this concept to find widespread applicability in the discovery of novel bioactive molecules such as chemical probes and small molecule drugs.

Next-generation encoded small-molecule libraries

ACS Spring 2022

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