{
  "abstract": "Heck coupling remains challenging in solid-phase peptide synthesis (SPPS) and diversification of combinatorial small-molecule libraries. The intermolecular Heck reaction has not yet been implemented in SPPS, owing to the lack of effective catalysts achieving broad substrate scopes on resin-bound peptides. Peptide-encoded libraries (PELs) enable high-throughput identification of small-molecule ligands to protein targets and allow access to structurally diverse chemotypes. Here, we introduce a covalent PEL (coPEL) platform that incorporates on-resin Heck coupling to derivatize cysteine-reactive scaffolds during solid-phase library synthesis. We leverage the specific reactivity of palladium catalysts derived from tBuDavePhos to enable intermolecular on-resin Heck coupling reactions to rapidly diversify covalent acrylamide warheads. The optimized reaction conditions are high-yielding across a broad range of (hetero)aryl halides and acrylamides, ensuring robust performance and versatility within the coPEL platform. Screening a model coPEL against the epidermal growth factor receptor (EGFR) tyrosine kinase yielded original low-micromolar covalent inhibitors. This work establishes intermolecular on-resin Heck coupling as a practical tool for SPPS and expands the accessible chemical space for covalent ligand discovery.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Chemistry, Massachusetts Institute of Technology Cambridge MA 02139 USA",
    "Calico Life Sciences LLC South San Francisco CA 94080 USA",
    "The Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology Cambridge MA 02139 USA",
    "Center for Environmental Health Sciences, Massachusetts Institute of Technology Cambridge MA 02139 USA"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 11,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Ching-Pei Hsu",
      "orcid": "0000-0002-9212-3504"
    },
    {
      "affs": [
        0
      ],
      "name": "Michael Desgagné",
      "orcid": "0000-0002-0671-6283"
    },
    {
      "affs": [
        0
      ],
      "name": "Simon L. Rössler",
      "orcid": "0000-0002-5057-0576"
    },
    {
      "affs": [
        0
      ],
      "name": "Nathalie M. Grob",
      "orcid": "0000-0003-1031-5105"
    },
    {
      "affs": [
        0
      ],
      "name": "Charlotte E. Farquhar"
    },
    {
      "affs": [
        0
      ],
      "name": "Andrei Loas",
      "orcid": "0000-0001-5640-1645"
    },
    {
      "affs": [
        1
      ],
      "name": "Zena D. Jensvold"
    },
    {
      "affs": [
        1
      ],
      "name": "Hannah T. Baddock"
    },
    {
      "affs": [
        1
      ],
      "name": "Matthew Bratkowski"
    },
    {
      "affs": [
        1
      ],
      "name": "Aaron H. Nile",
      "orcid": "0000-0002-7370-8769"
    },
    {
      "affs": [
        0,
        2,
        3
      ],
      "name": "Bradley L. Pentelute",
      "orcid": "0000-0002-7242-801X"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/0aczpkweyr3ax.bib",
  "cited_by": 0,
  "doi": "10.1039/d6sc05323h",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13548087/",
  "id": "0aczpkweyr3ax",
  "issns": [
    "2041-6520",
    "2041-6539"
  ],
  "landing_url": "https://doi.org/10.1039/d6sc05323h",
  "language": "en",
  "licence": "CC-BY-NC-3.0",
  "licence_label": "CC BY-NC 3.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc/3.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Chemistry"
    ],
    [
      "openalex",
      "1605|Catalytic Cross-Coupling Reactions"
    ]
  ],
  "openalex": "W7204136172",
  "pdf_url": null,
  "pmcid": "PMC13548087",
  "pmid": "42707419",
  "published": "2026-08-25",
  "publisher": "Royal Society of Chemistry",
  "ris": "https://research.draconitic.com/paper/0aczpkweyr3ax.ris",
  "sources": [
    {
      "first_seen": "2026-10-31T12:23:45Z",
      "native_id": "PMC13548087",
      "source": "pmc",
      "url": "https://doi.org/10.1039/d6sc05323h"
    }
  ],
  "subjects": [
    {
      "field": "chemistry",
      "origin": "openalex:1605|Catalytic Cross-Coupling Reactions",
      "subfield": "organic"
    }
  ],
  "title": "On-resin Heck coupling enables small-molecule ligand discovery with covalent peptide-encoded libraries",
  "title_text": "On-resin Heck coupling enables small-molecule ligand discovery with covalent peptide-encoded libraries",
  "type": "peer-reviewed",
  "updated_at": "2026-11-01T12:20:52Z",
  "url": "https://research.draconitic.com/paper/0aczpkweyr3ax",
  "venue": "Chemical Science",
  "versions": []
}