2. Academic Validation
  3. Untargeted Diversity-Oriented Synthesis for the Discovery of New Antitumor Agents: An Integrated Approach of Inverse Virtual Screening, Bioinformatics, and Omics for Target Deconvolution

Untargeted Diversity-Oriented Synthesis for the Discovery of New Antitumor Agents: An Integrated Approach of Inverse Virtual Screening, Bioinformatics, and Omics for Target Deconvolution

  • J Med Chem. 2025 Aug 14;68(15):16483-16517. doi: 10.1021/acs.jmedchem.5c01344.
Tania Ciaglia 1,  Valeria Napolitano 1,  Maria Rosaria Miranda 1 2,  Danila La Gioia 1 2,  Simona Musella 1,  Aniello Schiano Moriello 3,  Fabrizio Merciai 1,  Veronica Di Sarno 1,  Simona De Vita 1,  Ester Colarusso 1,  Gerardina Smaldone 1,  Francesca Di Matteo 1,  Eduardo Maria Sommella 1,  Poulami Kumar 3,  Marco Allarà 3,  Alessia Ligresti 3,  Isabel M Gomez-Monterrey 4,  Giuseppe Bifulco 1,  Gianluigi Lauro 1,  Pietro Campiglia 1,  Carmine Ostacolo 1,  Vincenzo Vestuto 1,  Alessia Bertamino 1
Affiliations

Affiliations

  • 1 Department of Pharmacy, University of Salerno, Via G. Paolo II 132, 84084 Fisciano, Salerno, Italy.
  • 2 PhD Program in Drug Discovery and Development, University of Salerno, Via G. Paolo II 132, 84084 Fisciano, Salerno, Italy.
  • 3 Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Comprensorio Olivetti, Via Campi Flegrei, 34, 80078 Pozzuoli, Naples, Italy.
  • 4 Department of Pharmacy, University Federico II of Naples, Via D. Montesano 49, 80131 Naples, Italy.
PMID: 40705771 DOI: 10.1021/acs.jmedchem.5c01344
Abstract

Molecular diversity is one of the most pursued objectives in drug discovery, and diversity-oriented synthesis (DOS) perfectly responds to the achievement of this goal. In this paper, we describe a DOS approach applied to the antitumor field with the aim of identifying new Anticancer structures and their associated targets. To accomplish this ambitious project, after an initial stage of phenotypic evaluation, we set up an integrated platform of inverse virtual screening (IVS), bioinformatics, and omics to predict the biological targets of the most promising compounds 31 and 63. Several proteins emerged from this study, and the most interesting ones were assessed by biophysical and in cellulo experiments, leading to the validation of six targets involved in calcium regulation, endoplasmic reticulum stress, and Apoptosis. This work allowed us to identify two hit compounds with an interesting antitumor mechanism, but principally, to validate our platform as a fruitful tool for untargeted DOS campaigns.

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