{
  "abstract": "N6-Adenosine methylation (m6A) is the most abundant post-transcriptional modification of mRNA. The reader proteins YTHDF1, YTHDF2, and YTHDF3 recognize m6A-RNA in the cytosol. Here, we present a protein structurebased medicinal chemistry campaign that resulted in the pan-YTHDF inhibitor 34, which shows for YTHDF2 an equilibrium dissociation constant (Kd) of 0.14 µM determined by calorimetry. Compound 34 binds the three YTHDF paralogs with comparable affinity, while being selective against YTHDC1 and YTHDC2. The high-resolution crystal structures of the complex of YTHDF2 with six members of the series validate the structure-based design. Using the structural information, we designed the advanced compound 31 (IC50 = 0.22 μM for YTHDF2, according to TR-FRET) and a negative control, i.e., its methylated analogue 31b (IC50 > 100 μM for the three YTHDF paralogs, according to TR-FRET). The cellular thermal shift assay (CETSA) provides evidence of YTHDF2 target engagement in cells for the advanced compounds 34 and 31, while the negative control 31b is inactive in CETSA. Compounds 34 and 31 at low-µM concentration inhibit the proliferation of the acute myeloid leukemia (AML) cell lines MOLM-13 and THP-1. Importantly, the inhibition of the YTHDF readers by 31 increases the level and stability of the transcript of tumour necrosis factor receptor superfamily member 1B. This renders THP-1 cells more sensitive to tumour necrosis factor-α-induced toxicity. Thus, ligand 34 and the pair 31 and 31b are tool compounds for studying the biological roles of the cytosolic YTHDF readers and their involvement in AML.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": null,
  "arxiv": null,
  "author_total": 9,
  "authors": [
    {
      "name": "Francesco Errani",
      "orcid": "0009-0004-4658-9022"
    },
    {
      "name": "Francesco Nai"
    },
    {
      "name": "Elena Bochenkova"
    },
    {
      "name": "Marcin Herok"
    },
    {
      "name": "Annalisa Invernizzi"
    },
    {
      "name": "Rajiv Kumar Bedi"
    },
    {
      "name": "Yaozong Li"
    },
    {
      "name": "František Zálešák"
    },
    {
      "name": "Amedeo Caflisch"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/1xqfawp0p7kbc.bib",
  "cited_by": 0,
  "doi": "10.26434/chemrxiv.15009836/v1",
  "fulltext_url": null,
  "id": "1xqfawp0p7kbc",
  "issns": [],
  "landing_url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009836/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": "W7220472684",
  "pdf_url": "https://chemrxiv.org/doi/pdf/10.26434/chemrxiv.15009836/v1",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-05",
  "publisher": "American Chemical Society (ACS)",
  "ris": "https://research.draconitic.com/paper/1xqfawp0p7kbc.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:22Z",
      "native_id": "10.26434/chemrxiv.15009836",
      "source": "chemrxiv",
      "url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009836/v1"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|RNA modifications and cancer",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Structure-Based Design of Potent Pan-YTHDF Ligands",
  "title_text": "Structure-Based Design of Potent Pan-YTHDF Ligands",
  "type": "preprint",
  "updated_at": "2026-10-30T12:17:22Z",
  "url": "https://research.draconitic.com/paper/1xqfawp0p7kbc",
  "venue": "ChemRxiv",
  "versions": []
}