Ching-Pei Hsu, Michael Desgagné, Simon L. Rössler, Nathalie M. Grob, Charlotte E. Farquhar, Andrei Loas, Zena D. Jensvold, Hannah T. Baddock, Matthew Bratkowski, Aaron H. Nile, and Bradley Pentelute
ChemRxiv, 2026
doi:10.26434/chemrxiv-2026-z6vkt
The use of encoding tags in combinatorial libraries accelerates hit generation by enabling high-throughput identification of small-molecule ligands. Peptide-encoded libraries (PELs) support the selection of structurally diverse small-molecule binders to proteins of interest. Here, we introduce a covalent PEL (coPEL) platform that incorporates cysteine-reactive scaffolds to identify irreversible protein binders. We leverage the chemical stability of PELs and the selective reactivity of palladium catalysts derived from dialkylbiaryl phosphine ligands to enable solid-phase Heck coupling reactions to rapidly diversify covalent acrylamide warheads. The optimized reaction conditions are high-yielding across a broad range of (hetero)aryl halides, ensuring robust performance and versatility within the coPEL platform. Screening a coPEL against the epidermal growth factor receptor (EGFR) tyrosine kinase, a key oncology target, yielded covalent small-molecule inhibitors with low-micromolar potency in vitro. This approach provides a complementary strategy for targeting diverse proteins and developing new classes of covalent inhibitors.
