2. Academic Validation
  3. Identification of pyrazolo-piperidinone derivatives targeting YAP-TEAD interface 3 as anticancer agents through integrated virtual screening and mass spectrometry proteomics

Identification of pyrazolo-piperidinone derivatives targeting YAP-TEAD interface 3 as anticancer agents through integrated virtual screening and mass spectrometry proteomics

  • Eur J Med Chem. 2025 Dec 15:300:118056. doi: 10.1016/j.ejmech.2025.118056.
Laura Scalvini 1,  Lorenzo Tagliazucchi 2,  Gian Marco Elisi 1,  Dana Zappaterra 2,  Maria Gaetana Moschella 3,  Sebastian Fantini 4,  Daniele Aiello 2,  Remo Guerrini 5,  Valentina Albanese 5,  Salvatore Pacifico 5,  Ludovica Lopresti 6,  Giulia Malpezzi 3,  Giulia Saporito 2,  Stefania Ferrari 2,  Michele Lamesta 7,  Lorena Losi 2,  Cecilia Pozzi 8,  Stefano Mangani 6,  Gaetano Marverti 4,  Alberto Venturelli 2,  Glauco Ponterini 2,  Domenico D'Arca 9,  Marco Mor 10,  Maria Paola Costi 11
Affiliations

Affiliations

  • 1 Dipartimento di Scienze degli Alimenti e del Farmaco, Università degli Studi di Parma, Parco Area delle Scienze 27/A, I, 43124, Parma, Italy.
  • 2 Department of Life Sciences, University of Modena and Reggio Emilia, Via G. Campi 103, 41125, Modena, Italy.
  • 3 Department of Life Sciences, University of Modena and Reggio Emilia, Via G. Campi 103, 41125, Modena, Italy; Clinical and Experimental Medicine (CEM) PhD Program, University of Modena and Reggio Emilia, Via G. Campi 287, 41125, Modena, Italy.
  • 4 Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Via G. Campi 287, 41125, Modena, Italy.
  • 5 Dept. of Medical Sciences and Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, 44121, Ferrara, Italy.
  • 6 Department of Biotechnology, Chemistry and Pharmacy, Department of Excellence 2018-2020, University of Siena, via Aldo Moro 2, 53100, Siena, Italy.
  • 7 Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia, Modena, Italy; Department of Precision Medicine in Medical, Surgical and Critical Care (Me.Pre.C.C.) PhD in Precision Medicine, University of Palermo, Palermo, Italy.
  • 8 Department of Biotechnology, Chemistry and Pharmacy, Department of Excellence 2018-2020, University of Siena, via Aldo Moro 2, 53100, Siena, Italy; Consorzio Interuniversitario Risonanze Magnetiche di Metallo Proteine (CIRMMP), Via Luigi Sacconi 6, 50019, Sesto Fiorentino (FI), Italy.
  • 9 Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Via G. Campi 287, 41125, Modena, Italy. Electronic address: domenico.darca@unimore.it.
  • 10 Dipartimento di Scienze degli Alimenti e del Farmaco, Università degli Studi di Parma, Parco Area delle Scienze 27/A, I, 43124, Parma, Italy. Electronic address: marco.mor@unipr.it.
  • 11 Department of Life Sciences, University of Modena and Reggio Emilia, Via G. Campi 103, 41125, Modena, Italy. Electronic address: mariapaola.costi@unimore.it.
PMID: 40907380 DOI: 10.1016/j.ejmech.2025.118056
Abstract

The transcriptional activity of TEAD4 (transcriptional enhancer associated domain proteins), one of the final effectors of the Hippo pathway, can be dysregulated or mutated in Cancer. Consequently, targeting the interaction between TEAD and its co-activator YAP (Yes Associated Protein) to disrupt the YAP:TEAD (Y:T) heterodimer has emerged as a promising anti-cancer strategy. Therefore, in this study, we aimed to identify novel scaffolds targeting the TEAD Interface 3 surface as effective Anticancer agents against colorectal and ovarian Cancer. Employing virtual screening, molecular dynamics, computational ADME-T prediction, and synthetic chemistry, we initially identified novel pyrazolo-piperidinone compounds exhibiting binding affinities (Kd) between 0.6 and 10 μM towards TEAD4 Interface 3 in a fluorescence anisotropy assay, with 6a as the initial lead for a library of 20 compounds. A few of them demonstrated effective and well-characterized cellular antiproliferative activity against HCT116 and A2780 Cancer cells. They demonstrated efficacy against colorectal Cancer cells resistant to the KRAS-dependent clinical candidate IAG933 and confirmed the ability to inhibit TEAD4 target genes expression. Mass spectrometry-based proteomics of HCT116 cells treated with verteporfin and 6a analogs revealed a proteome modulation consistent with an anti-TEAD mechanism of action, revealing the downregulation of CTGF and TGF-β1. Bioinformatic metabolic pathway analysis further differentiated the mechanism of action of the 6a analogs from verteporfin, a known indirect modulator of the Y:T complex. These findings establish the pyrazolo-piperidinone class as novel Y:T disruptors and provide insights into their metabolic impact on downstream effectors, offering a valuable framework for future hit-to-lead optimization and mechanism of action studies.

Keywords

Anticancer agents; Fluorescence anisotropy; MS proteomics; Phenotypic screening; Pyrazolo-piperidinone derivatives; TEAD targeting.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-179706
    YAP-TEAD相互作用抑制剂
    YAP
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