Yulong An ,  Ruolan Zhou ,  Xiang Li

ACS Medicinal Chemistry Letters 

DOI: 10.1021/acsmedchemlett.5c00738

Abstract

DNA-encoded library (DEL) technology has emerged as a transformative platform for discovering chemical inducers of proximity (CIPs), addressing challenges in both degrader and non-degrader CIP development. This Microperspective analyzes the results of recent DEL technology screens (2021–2025) to enable medicinal chemistry programs, focusing on CIP development including CIP-focused DELs, DEL-derived ligands for proteins of interest (POIs) and E3 ligase in rational CIP design, and directly functional CIP identification. Finally, we address current limitations of DEL technology in CIP research and outline future directions. This Microperspective underscores DEL’s pivotal role in advancing CIP discovery, providing actionable insights for addressing “undruggable” targets and accelerating translational research in chemical biology and medicinal chemistry.

Summary

This MicroPerspective reviews recent advances (2021–2025) in DNA-encoded library (DEL) technology for discovering chemical inducers of proximity (CIPs), spanning both degraders (e.g., PROTACs, molecular glue degraders) and non-degrader modalities (e.g., protein stabilization, subcellular relocalization, transcriptional activation). It synthesizes three key strategies: (1) CIP-focused DELs (CIP-DELs), enabling simultaneous dual-target (POI + E3 ligase) selection to directly identify cooperatively binding bifunctional compounds; (2) Conversion of DEL-derived POI/E3 ligands—leveraging well-defined DNA attachment sites as “exit vectors”—into functional CIPs; and (3) Discovery of non-degradative CIPs, including FKBP12-recruiting molecular glues and function-driven DEL screening (e.g., direct ubiquitination readout). DEL overcomes longstanding limitations of traditional HTS—including library size, cost, and scarcity of E3 ligands—thereby accelerating CIP development against “undruggable” targets.

Highlights

• Dual-Target CIP-DEL Screening: CRBN- or VHL-targeted DELs enable concurrent selection against POIs and E3 ligases, directly identifying ternary complex stabilizers with high cooperativity (e.g., BRD4/BRD2-selective PROTACs, BRD9 molecular glue).
• Ligand-to-CIP Conversion Paradigm: DEL-derived ligands for ERα, MAGE-A3, PIN1, DNPH1, and TRIM21 were optimized and converted into functional PROTACs or TrimTACs; the DNA attachment site serves as a built-in, precise “exit vector” for linker conjugation.
• Expansion to Non-Degradative Functions: An FKBP12-biased CIP-DEL identified a molecular glue that stabilizes the Crohn’s disease-associated ATG16L1 T300A variant; function-driven DEL screening (in presence of E1/E2/ATP) directly enriches ubiquitination-competent PROTACs, eliminating affinity-only false positives.
• New Frontier: RNA Targets: DEL screening against RNase L led to the design of RiboTACs targeting pre-miR-21—extending CIP therapeutics to RNA biology.

Conclusion

DEL technology has evolved from a single-target ligand discovery platform into a central engine driving the discovery of the full spectrum of CIPs—from degraders to non-degraders, and from proteins to RNA. Its core advantages lie in vast chemical space coverage, barcode-enabled precise hit identification, and intrinsic structural information (e.g., defined exit vectors). Future directions include integrating AI for POI–E3 interface–guided library design, developing robust in-cell DEL screening, expanding the repertoire of E3 ligase ligands, and strengthening functional phenotypic and preclinical translational studies—to fully unlock the therapeutic potential of CIPs against “undruggable” targets.