2. Academic Validation
  3. Targeting Class I Histone Deacetylases Triggers Antitumor Responses in Colorectal Cancer In Vitro and In Vivo

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

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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