{
  "abstract": "Dysregulation of insulin-like growth factor (IGF) signaling contributes to diverse human diseases. Therapeutic strategies have largely targeted the IGF-1 receptor, but the complexity of the IGF system has limited their clinical efficacy. Pregnancy-associated plasma protein-A (PAPP-A) is a secreted metalloproteinase that regulates local IGF signaling through proteolytic cleavage of IGF-binding proteins (IGFBPs) and represents an attractive therapeutic target. Here, we report the first synthetic PAPP-A inhibitors designed to target the enzyme active site using an IGFBP-5-derived anchor sequence. Replacing the scissile bond with phosphinate or phosphonate moieties yielded potent and selective PAPP-A inhibitors. Cryo-electron microscopy revealed the molecular basis of inhibition and key active-site interactions. The compounds inhibited cleavage of IGFBP-4 and IGFBP-5, two physiological PAPP-A substrates. They suppressed IGF-1 signaling in A549 lung cancer cells, with efficacy comparable to the endogenous PAPP-A inhibitor stanniocalcin-1. They also inhibited Papp-aa-dependent IGF signaling and cell proliferation in wild-type and stc1a-/- mutant zebrafish in vivo in a dose-dependent manner. Together, these findings establish the first class of synthetic, selective PAPP-A inhibitors capable of modulating IGF signaling. They provide new chemical tools for studying and modulating pathological IGF signaling and offer new directions for developing PAPP-A-targeted therapeutic strategies.",
  "abstract_shown": true,
  "affiliations": [
    "Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 13,
  "authors": [
    {
      "name": "A. Kertisova"
    },
    {
      "name": "S.-W. Shih"
    },
    {
      "name": "N. S. Kirk"
    },
    {
      "name": "J. Picha"
    },
    {
      "name": "A. Rucklova"
    },
    {
      "name": "J. Kozak"
    },
    {
      "name": "K. Mrzilkova"
    },
    {
      "name": "M. Lubos"
    },
    {
      "name": "E. Tloustova"
    },
    {
      "name": "M. Budesinsky"
    },
    {
      "name": "C. Duan"
    },
    {
      "name": "J. Jiracek"
    },
    {
      "affs": [
        0
      ],
      "name": "I. Selicharova"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/4haba4phfdwt4.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.30.755852",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.30.755852v1.full",
  "id": "4haba4phfdwt4",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.30.755852v1",
  "language": null,
  "licence": "CC-BY-NC",
  "licence_label": "CC BY-NC",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "biochemistry"
    ],
    [
      "openalex",
      "2712|Growth Hormone and Insulin-like Growth Factors"
    ]
  ],
  "openalex": "W7204171096",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.30.755852v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-30",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/4haba4phfdwt4.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:25:46Z",
      "native_id": "10.64898/2026.09.30.755852",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.30.755852v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2712|Growth Hormone and Insulin-like Growth Factors",
      "subfield": "endocrinology-metabolism"
    }
  ],
  "title": "Synthetic inhibitors of pregnancy-associated plasma protein-A regulate IGF-1 signaling in vitro and in vivo",
  "title_text": "Synthetic inhibitors of pregnancy-associated plasma protein-A regulate IGF-1 signaling in vitro and in vivo",
  "type": "preprint",
  "updated_at": "2026-10-30T12:25:46Z",
  "url": "https://research.draconitic.com/paper/4haba4phfdwt4",
  "venue": "bioRxiv",
  "versions": []
}