Highly pure DNA-encoded chemical libraries by dual-linker solid-phase synthesis

Abstract

The first drugs discovered using DNA-encoded chemical library (DEL) screens have entered late-stage clinical development. However, DEL technology as a whole still suffers from poor chemical purity resulting in suboptimal performance. In this work, we report a technique to overcome this issue through self-purifying release of the DEL after magnetic bead–based synthesis. Both the first and last building blocks of each assembled library member were linked to the beads by tethers that could be cleaved by mutually orthogonal chemistry. Sequential cleavage of the first and last tether, with washing in between, ensured that the final library comprises only the fully complete compounds. The outstanding purity attained by this approach enables a direct correlation of chemical display and encoding, allows for an increased chemical reaction scope, and facilitates the use of more diversity elements while achieving greatly improved signal-to-noise ratios in selections.

Isothiocyanate intermediates facilitate divergent synthesis of N-heterocycles for DNA-encoded libraries

“…DNA-encoded library (DEL) technology is a powerful method for hit discovery in the pharmaceutical industry, 1 with an increasing number of DEL-derived lead compounds advancing to clinical trials. 2 DEL's chemical space and structural diversity, which are responsible for successful hit discovery, are prompting the expansion of the DNA-compatible reaction toolbox.…”