Targeting Class I Histone Deacetylases Triggers Antitumor Responses in Colorectal Cancer In Vitro and In Vivo

  • J Med Chem. 2026 Jan 22;69(2):1049-1074. doi: 10.1021/acs.jmedchem.5c02237.
Gabriele Carullo  1 ,  Federica Falbo  2 ,  Valeria Tudino  1 ,  Jiazhao Song  3 ,  Marianna Fava  1 ,  Anna Fontana  1 ,  Adrian Koch  3 ,  Anita Heiß  3 ,  Katharina Erlenbach-Wuensch  4 ,  Giovanna Panzeca  1 ,  Simone Brogi  5 ,  Alessia Bichicchi  6 ,  Simona Saponara  6 ,  Fabio Fusi  1 ,  Fabrizio Vincenzi  7 ,  Katia Varani  7 ,  Martina Cappello  7 ,  Silvia Pasquini  7 ,  Anna Ramunno  8 ,  Giacomo Pepe  8 ,  Stefania Butini  1 ,  Francesca Aiello  2 ,  Sandra Gemma  1 ,  Regine Schneider-Stock  3  9 ,  Giuseppe Campiani  1
Affiliations
  • 1. Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, Siena 53100, Italy.
  • 2. Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Edificio Polifunzionale, Rende, CS 87036, Italy.
  • 3. Experimental Tumorpathology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsstrasse 22, Erlangen 91054, Germany.
  • 4. Institute of Pathology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsstrasse 22, Erlangen 91054, Germany.
  • 5. Department of Pharmacy, University of Pisa, Via Bonanno 6, Pisa 56126, Italy.
  • 6. Department of Life Sciences, University of Siena, Via Aldo Moro 2, Siena 53100, Italy.
  • 7. Department of Translational Medicine, University of Ferrara, via Luigi Borsari 46, Ferrara 44121, Italy.
  • 8. Department of Pharmacy, University of Salerno, Campus di Fisciano, Via Giovanni Paolo II 132, Fisciano, SA 84084 Italy.
  • 9. Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Bavarian Cancer Research Center (BZKF), Erlangen 91054, Germany.
PMID: 41486684 DOI: 10.1021/acs.jmedchem.5c02237
Abstract

Class I histone deacetylases (HDACs) are frequently overexpressed in colorectal Cancer (CRC). Combining computational, synthetic, and biological efforts, we developed novel o-aminobenzamide-based HDAC inhibitors (HDACis) optimized for class I enzyme-specific targeting. Compounds 5d and 5i emerged as lead candidates, showing strong antiproliferative effects in CRC cells with low toxicity in healthy colon epithelium. Both compounds disrupted the G2/M checkpoint through distinct mechanisms. 5i, although less potent (HDAC1 IC50 = 1508 nM), retained selectivity, upregulated p21, and triggered pronounced Apoptosis. 5d (Colrestat), one of the most selective class I HDACis to date (HDAC1 IC50 = 41.2 nM, HDAC2 IC50 = 52.5 nM, and HDAC3 IC50 = 74.3 nM), induced H3K9 acetylation, p21 upregulation, and G2/M arrest. The short-term in vitro effects of 5d were modulated by a compensatory upregulation of Autophagy. However, in long-term, this protective mechanism becomes insufficient to sustain tumor survival, resulting in strong antitumor efficacy in vivo in the CAM assay for both compounds even outperforming entinostat.

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