Diversity-oriented synthesis has been used to enrich small molecule screening collections with unusual scaffold architectures, well defined stereochemistry and high sp3 content. As a result, novel mechanisms of action have been elucidated, often opening exciting avenues in drug discovery. Some barriers to the more widespread adoption of such screening collections by the community are cost and time — with many synthetic routes being long and complex. DNA-encoded libraries (DELs) have emerged as an effective and highly efficient screening tool. However, the majority of published syntheses are limited to the constraints of working at low concentration, in an aqueous environment, with sensitive DNA present. As such, most DELs are composed primarily of peptides and sp2-rich molecules. As part of a deep collaboration between Novartis and the Schreiber lab we endeavor to combine modern synthetic chemistry with the DEL format. The resulting collection of structurally diverse compounds will serve as a high quality tool for early phase drug discovery. Moreover, library production will be performed on sufficient scale to share with the scientific community. We foresee this resource enabling many future projects. This presentation will cover the design of the library, the synthetic strategy employed to produce it, and a roadmap for how we envisage this ambitious open-source tool being implemented for your projects.

DOSEDO: Diversity-oriented synthesis encoded by deoxyoligonucleotides

2019 Fall National Meeting

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