Discovery of a Novel Covalent Inhibitor Using DEL

With advancements in drug design, there is resurging interest in drugs that form covalent bonds with their targets. Covalent drugs have the potential to provide enhanced potency and prolonged duration of action compared to non-covalent drugs. Emerging areas of interest include the development of reversible covalent inhibitors, covalent degraders, and covalent targeting of non-cysteine amino acid residues.

At the 2025 Society for Laboratory Automation and Screening (SLAS) conference in San Diego, WuXi AppTec presented a poster describing the identification of novel covalent inhibitors (potentially targeting a non-cysteine amino acid), using irreversible and reversible covalent DNA-encoded libraries (DEL). Further on-DNA and off-DNA compound resynthesis and validation confirmed that these compounds have relatively high binding potency, demonstrating that DEL can be a robust method for covalent inhibitor identification, providing vast chemical space and SAR information.