{
  "abstract": "Genetic perturbation has been central to defining the functions of RNA modification binding proteins (readers), but knockout approaches remove the entire protein and cannot readily distinguish modification-dependent reader activity from other protein-associated functions. Small molecules provide an orthogonal strategy by directly perturbing the reader protein–RNA recognition event while preserving the reader protein. Here we report DF142, a cell-active pan-YTHDF chemical probe developed through an m6A-anchored design strategy. Structure-guided optimization yielded a high-affinity ligand that engages endogenous YTHDF proteins, blocks YTHDF–m6A RNA recognition, and displays a favorable selectivity profile. In mouse B cells, DF142 closely recapitulated the transcriptional effects of genetic Ythdf1/2 loss but induced minimal effects in Ythdf1/2-deficient cells at the applied dose range, distinguishing m6A-dependent from putative m6A-independent programs. In AML cells, application of DF142 revealed a leukemia-relevant RNA program associated with YTHDF–m6A interactions. Its activity in cancer cells and mouse models further demonstrates the utility of DF142 for interrogating YTHDF function in disease-relevant settings. Together, these findings establish DF142 as a chemical probe for dissecting m6A-dependent YTHDF biology.",
  "abstract_shown": true,
  "affiliations": [
    "Institute for Biophysical Dynamics",
    "University of Chicago",
    "Howard Hughes Medical Institute",
    "Stowers Institute for Medical Research",
    "Department of Biochemistry and Molecular Biology",
    "Medical Scientist Training Program",
    "Institute of Microbiology",
    "Chinese Academy of Sciences"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 17,
  "authors": [
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Wenlong Li"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Linda Zhang"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Zhong Zheng"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Pingluan Wang"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Yutao Zhao"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Yanming Chen"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Hui-lung Sun"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Fei Ji"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Peng Xia"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Xinyuan Ma"
    },
    {
      "affs": [
        3
      ],
      "name": "Xinjian Mao"
    },
    {
      "affs": [
        4,
        1
      ],
      "name": "Bixia Zhang"
    },
    {
      "affs": [
        0,
        1,
        2,
        5
      ],
      "name": "Yusuf Noffel"
    },
    {
      "affs": [
        3
      ],
      "name": "Linheng Li"
    },
    {
      "affs": [
        4,
        1
      ],
      "name": "Minglei Zhao"
    },
    {
      "affs": [
        6,
        7
      ],
      "name": "Liangliang Wang"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Chuan He"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/e9hj3v2c8qh7p.bib",
  "cited_by": 0,
  "doi": "10.26434/chemrxiv.15009365/v1",
  "fulltext_url": null,
  "id": "e9hj3v2c8qh7p",
  "issns": [],
  "landing_url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009365/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",
      "1312|RNA modifications and cancer"
    ]
  ],
  "openalex": "W7214067266",
  "pdf_url": "https://chemrxiv.org/doi/pdf/10.26434/chemrxiv.15009365/v1",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-23",
  "publisher": "American Chemical Society (ACS)",
  "ris": "https://research.draconitic.com/paper/e9hj3v2c8qh7p.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:21Z",
      "native_id": "10.26434/chemrxiv.15009365",
      "source": "chemrxiv",
      "url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009365/v1"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|RNA modifications and cancer",
      "subfield": "molecular-biology"
    }
  ],
  "title": "A Pan-YTHDF Probe Enables Chemical Modulation and Dissection of RNA m6A Reader Programs",
  "title_text": "A Pan-YTHDF Probe Enables Chemical Modulation and Dissection of RNA m6A Reader Programs",
  "type": "preprint",
  "updated_at": "2026-10-30T12:17:21Z",
  "url": "https://research.draconitic.com/paper/e9hj3v2c8qh7p",
  "venue": "ChemRxiv",
  "versions": []
}