{
  "abstract": "Three-dimensional molecular shape is a fundamental determinant of protein recognition, yet chemical discovery is often biased toward regio- and stereoisomers that are more readily accessible by synthesis. Here we overcome this constraint using radical cross-coupling (RCC), converting stereoprobe synthesis from selective sampling into exhaustive exploration of three-dimensional chemical space. By combining stereorandomizing and stereopreserving RCC manifolds, we constructed complete piperidine and pyrrolidine matrices (40 and 24 members, respectively) encompassing every theoretically possible regio- and stereoisomer of the corresponding disubstituted scaffolds and expanded these collections to 108 covalent stereoprobes from a small set of readily available precursors. Proteome-wide activity-based protein profiling (ABPP) revealed highly differentiated engagement across regio- and stereoisomers that could further be diversified by changing the covalent reactive group. Selected engagements were structurally characterized by X-ray crystallography, and extension to complementary protein-directed ABPP further expanded the observable ligandability landscape. These findings establish RCC as a practical strategy for removing synthetic bias from stereochemical exploration and identified stereoselective small molecule-protein engagements that could have been missed by conventional non-exhaustive screening.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Chemistry",
    "Scripps Research",
    "School of Chemistry and Chemical Engineering",
    "South China University of Technology",
    "Vividion Therapeutics, Inc.",
    "Automated Synthesis Facility"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 27,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Yin Li"
    },
    {
      "affs": [
        0,
        1,
        2,
        3
      ],
      "name": "Jiayan He"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Jeffery J. Yu"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Jiawei Sun"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Rajan R. Gollapudi"
    },
    {
      "affs": [
        4
      ],
      "name": "Christopher A. Toth"
    },
    {
      "affs": [
        4
      ],
      "name": "Steffen M. Bernard"
    },
    {
      "affs": [
        4
      ],
      "name": "Christie L. Eissler"
    },
    {
      "affs": [
        4
      ],
      "name": "Steven C Wang"
    },
    {
      "affs": [
        4
      ],
      "name": "Brian E. Nordin"
    },
    {
      "affs": [
        4
      ],
      "name": "Annabel Q. Ansel"
    },
    {
      "affs": [
        4
      ],
      "name": "Connor Scheuerman"
    },
    {
      "affs": [
        4
      ],
      "name": "Tracey Nguyen"
    },
    {
      "affs": [
        4
      ],
      "name": "Ann Shih"
    },
    {
      "affs": [
        4
      ],
      "name": "Cody L. Fullenwider"
    },
    {
      "affs": [
        4
      ],
      "name": "Benjamin D. Horning"
    },
    {
      "affs": [
        4
      ],
      "name": "Jonathan Pollock"
    },
    {
      "affs": [
        4
      ],
      "name": "Matthew P. Patricelli"
    },
    {
      "affs": [
        4
      ],
      "name": "David S. Weinstein"
    },
    {
      "affs": [
        4
      ],
      "name": "Gabriel M. Simon"
    },
    {
      "affs": [
        4
      ],
      "name": "Brian N. Cook"
    },
    {
      "affs": [
        5,
        1
      ],
      "name": "Quynh N. Wong"
    },
    {
      "affs": [
        5,
        1
      ],
      "name": "Jillian E. Smith"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Benjamin F. Cravatt"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Yu Kawamata"
    },
    {
      "affs": [
        4
      ],
      "name": "Cian Kingston"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Phil S. Baran",
      "orcid": "0000-0001-9193-9053"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/3a0s46q0q4tx8.bib",
  "cited_by": 0,
  "doi": "10.26434/chemrxiv.15010428/v1",
  "fulltext_url": null,
  "id": "3a0s46q0q4tx8",
  "issns": [],
  "landing_url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010428/v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1605|Click Chemistry and Applications"
    ]
  ],
  "openalex": "W7221773215",
  "pdf_url": "https://chemrxiv.org/doi/pdf/10.26434/chemrxiv.15010428/v1",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-13",
  "publisher": "American Chemical Society (ACS)",
  "ris": "https://research.draconitic.com/paper/3a0s46q0q4tx8.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:24Z",
      "native_id": "10.26434/chemrxiv.15010428",
      "source": "chemrxiv",
      "url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010428/v1"
    }
  ],
  "subjects": [
    {
      "field": "chemistry",
      "origin": "openalex:1605|Click Chemistry and Applications",
      "subfield": "organic"
    }
  ],
  "title": "Radical Cross-Coupling Delivers Complete Sets of Saturated-Heterocyclic Regio- and Stereoprobes for Chemoproteomic Discovery",
  "title_text": "Radical Cross-Coupling Delivers Complete Sets of Saturated-Heterocyclic Regio- and Stereoprobes for Chemoproteomic Discovery",
  "type": "preprint",
  "updated_at": "2026-10-30T12:17:24Z",
  "url": "https://research.draconitic.com/paper/3a0s46q0q4tx8",
  "venue": "ChemRxiv",
  "versions": []
}