DNA-encoded library (DEL) screens have emerged as a powerful hit-finding tool for a number of biological targets. Herein, published hit-to-lead optimization studies following DEL screens are reviewed. Trends in molecular property changes from hit to lead are identified, and specific optimization tactics are exemplified in case studies. Across the studies, physicochemical property and structural changes post-DEL screening are similar to those which occur during hit-to-lead optimization following HTS screens. However, unique aspects of DEL – the limited synthetic methods which enable DEL synthesis, the linker effects at the DNA attachment point – impact the strategies and outcomes of hit-to-lead optimizations.

Trends in hit-to-lead optimization following DNA-encoded library screens

ACS Spring Meeting 2021

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