{
  "abstract": "Pin1 is a peptidyl-prolyl isomerase involved in key signalling pathways and upregulated in different cancers, including Multiple Myeloma (MM), where it is linked to poor prognosis/drug resistance. Despite its therapeutic relevance, Pin1 remains challenging to target with conventional inhibitors thereby motivating interest in Targeted Protein Degradation (TPD) strategies. All reported Pin1-PROTACs rely on covalent Pin1 ligands, leaving non-covalent degraders largely unexplored. Since PROTACs (PROteolysis TArgeting Chimeras) act catalytically/reversibly, non-covalent designs are attractive. Here, we describe the design/synthesis/evaluation of 12 non-covalent potential Pin1-PROTACs (P1-P12) based on reversible peptidomimetic ligand and in a prodrug form to allow cell permeability. Despite rational design, stability and measurable target engagement, P1-P12 displayed none or very limited degradation activity, with the most active molecule, P3, achieving only 39% of Pin1 depletion in MM cells. To confirm Pin1 degradability in MM, MM1.R cells were treated with the covalent PROTAC P1D-34, which induced robust dose-dependent degradation (DC₅₀ = 3.16 µM, DMAX = 90%). Overall, while demonstrating the feasibility of Pin1 depletion in MM, this work highlights the challenge of achieving effective Pin1 degradation with non-covalent micromolar ligands, underscores the current advantage of covalent engagement, and provides a foundation for the future development of non-covalent Pin1 degraders.",
  "abstract_shown": true,
  "affiliations": [
    "CNRS, BioCIS, CY Cergy Paris Université, Cergy Pontoise, France.",
    "CNRS, BioCIS, Université Paris-Saclay, Orsay, France.",
    "CPCV, ENS, PSL, CNRS, Sorbonne Université, Paris, France."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 10,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Lorenzo Meneghelli",
      "orcid": "0009-0009-5054-1335"
    },
    {
      "affs": [
        2
      ],
      "name": "Stephanie Davidson"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Ji-Hyung Choi",
      "orcid": "0009-0000-2398-1591"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Sami Mohammed Daddi Moussa",
      "orcid": "0009-0000-2729-2750"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Simon Nadal",
      "orcid": "0000-0002-0748-0284"
    },
    {
      "affs": [
        2
      ],
      "name": "Delphine Ravault"
    },
    {
      "affs": [
        2
      ],
      "name": "Ludovic Carlier",
      "orcid": "0000-0002-9036-6561"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Maud Larregola",
      "orcid": "0000-0002-9196-3552"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Julien Pytkowicz",
      "orcid": "0000-0002-8545-3046"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Chiara Zanato",
      "orcid": "0000-0002-9132-5120"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/376pzz4xk45t1.bib",
  "cited_by": 0,
  "doi": "10.1002/cbdv.71850",
  "fulltext_url": "https://europepmc.org/articles/PMC13685476",
  "id": "376pzz4xk45t1",
  "issns": [
    "1612-1872",
    "1612-1880"
  ],
  "landing_url": "https://europepmc.org/article/MED/42904861",
  "language": "eng",
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1312|Protein Degradation and Inhibitors"
    ]
  ],
  "openalex": "W7223158741",
  "pdf_url": "https://europepmc.org/articles/PMC13685476?pdf=render",
  "pmcid": "PMC13685476",
  "pmid": "42904861",
  "published": "2026-10-01",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/376pzz4xk45t1.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:57Z",
      "native_id": "MED:42904861",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42904861"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Protein Degradation and Inhibitors",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Exploring Non-Covalent Pin1-PROTACs Insights Into Degradation Efficiency in Multiple Myeloma Cell Line.",
  "title_text": "Exploring Non-Covalent Pin1-PROTACs Insights Into Degradation Efficiency in Multiple Myeloma Cell Line.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:19:57Z",
  "url": "https://research.draconitic.com/paper/376pzz4xk45t1",
  "venue": "Chemistry & biodiversity",
  "versions": []
}