Discovery of First-in-Class Carbonic Anhydrase/Histone Deacetylase Dual Inhibitors with Antiproliferative Activity in Cancer Cells

  • J Med Chem. 2025 Nov 13;68(21):22874-22895. doi: 10.1021/acs.jmedchem.5c01788.
Murat Bozdag  1 ,  Nabil Mroweh  1 ,  Alessia Raucci  2 ,  Andrea Angeli  1 ,  Silvia Peppicelli  3 ,  Alessio Biagioni  3 ,  Lido Calorini  3 ,  Daniela Trisciuoglio  4 ,  Rino Ragno  2 ,  Roberta Astolfi  2 ,  Lidia Giuliani  2 ,  Clemens Zwergel  2 ,  Sergio Valente  2 ,  Elena Andreucci  3 ,  Fabrizio Carta  1 ,  Antonello Mai  2  5 ,  Claudiu T Supuran  1
Affiliations
  • 1. Università Degli Studi di Firenze, Dipartimento Neurofarba, Sezione di Scienze Farmaceutiche E Nutraceutiche, Via Ugo Schiff 6, Sesto Fiorentino, Florence I-50019, Italy.
  • 2. Department of Drug Chemistry & Technologies, Sapienza University of Rome, P. le a Moro 5, Rome 00185, Italy.
  • 3. Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence 50134, Italy.
  • 4. Institute of Molecular Biology and Pathology (IBPM), National Research Council (CNR), Rome 00185, Italy.
  • 5. Pasteur Institute, Cenci-Bolognetti Foundation, Sapienza University of Rome, Piazzale Aldo Moro 5, Rome 00185 Italy.
PMID: 41150938 DOI: 10.1021/acs.jmedchem.5c01788
Abstract

This study reports in vitro evidence supporting a new class of compounds capable of independently targeting the tumor-associated human (h) Carbonic Anhydrase (CA; EC 4.2.1.1) and histone deacetylase (HDAC; EC 3.5.1.98) isoforms as first-in-class agents endowed with enhanced antiproliferative effects and safety profiles when compared to their constitutive counterparts as well as to clinically used drugs. The binding modes of both the CA- and HDAC-directed moieties were investigated through X-ray and molecular modeling experiments, respectively, thus delivering detailed Structure-Activity Relationship (SAR) knowledge.

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