Christopher A. Reiher; David P. Schuman; Nicholas Simmons; Scott E. Wolkenberg
ACS Med. Chem. Lett., 2021, 12, 3, 343-350
https://doi.org/10.1021/acsmedchemlett.0c00615

Abstract

DNA-encoded library (DEL) screens have emerged as a powerful hit-finding tool for a number of biological targets. In this Innovations article, we review published hit-to-lead optimization studies following DEL screens. 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 high throughputscreens (HTS). However, unique aspects of DEL—the combinatorial synthetic methods which enable DEL synthesis and the linker effects at the DNA attachment point—impact the strategies and outcomes of hit-to-lead optimizations.