Lulu Wen,Qingqing Zhang,Zhiqiang Duan,Rui Jin,Xiaojie Lu

ChemMedChem

DOI: 10.1002/cmdc.202501032

Abstract

DNA-encoded library (DEL) technology has emerged as a powerful tool to accelerate drug discovery, and its application has expanded to challenging targets such as E3 ubiquitin ligases, whose ligands are essential for the development of targeted therapies, including proteolysis-targeting chimeras (PROTACs). In this review, we summarize recent advances in the use of DELs for the discovery of small-molecule non-covalent E3 ligase ligands and discuss their advantages in hit-to-lead optimization and the design of targeted protein degradation systems. Furthermore, we highlight the potential and application basis of covalent DELs and DNA-encoded cyclic peptide libraries, which together outline promising future directions for DEL-based discovery of E3 ligase ligands. Emerging DEL-based strategies for the direct discovery and optimization of TPD molecules are also discussed.