Targeting Class I Histone Deacetylases Triggers Antitumor Responses in Colorectal Cancer In Vitro and In Vivo
Class I histone deacetylases (HDACs) are frequently overexpressed in colorectal cancer (CRC). Combining computational, synthetic, and biological efforts, we developed novel <i>o</i>-aminobenzamide-based HDAC inhibitors (HDACis) optimized for class I enzyme-specific targeting. Compounds <b>5d</b> and <b>5i</b> 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. <b>5i</b>, although less potent (HDAC1 IC<sub>50</sub> = 1508 nM), retained selectivity, upregulated p21, and triggered pronounced apoptosis. <b>5d</b> (<i>Colrestat</i>), one of the most selective class I HDACis to date (HDAC1 IC<sub>50</sub> = 41.2 nM, HDAC2 IC<sub>50</sub> = 52.5 nM, and HDAC3 IC<sub>50</sub> = 74.3 nM), induced H3K9 acetylation, p21 upregulation, and G2/M arrest. The short-term <i>in vitro</i> effects of <b>5d</b> 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 <i>in vivo</i> in the CAM assay for both compounds even outperforming entinostat.
Authors
- Stefania Butini (ORCID: https://orcid.org/0000-0002-8471-0880)
- Anna Fontana (ORCID: https://orcid.org/0000-0002-5091-8202)
- Anna Ramunno (ORCID: https://orcid.org/0000-0003-1089-2439)
- Silvia Pasquini (ORCID: https://orcid.org/0000-0001-9442-1428)
- Adrian Koch (ORCID: https://orcid.org/0000-0001-5387-4906)
- Martina Cappello
- Giacomo Pepe (ORCID: https://orcid.org/0000-0002-7561-2023)
- Federica Falbo
- Valeria Tudino (ORCID: https://orcid.org/0000-0001-9024-9835)
- Simona Saponara (ORCID: https://orcid.org/0000-0002-3831-8669)
- Giovanna Panzeca (ORCID: https://orcid.org/0000-0001-6479-7686)
- Francesca Aiello (ORCID: https://orcid.org/0000-0001-5912-3185)
- Gabriele Carullo (ORCID: https://orcid.org/0000-0002-1619-3295)
- Katia Varani
- Sandra Gemma (ORCID: https://orcid.org/0000-0002-8313-2417)
- Alessia Bichicchi
- Marianna Fava
- Jiazhao Song
- Fabio Fusi
- Fabrizio Vincenzi
- Simone Brogi
- Regine Schneider-Stock
- Giuseppe Campiani
- Katharina Erlenbach-Wuensch
- Anita Heiß
Institutions
- University of Siena (IT)
- University of Pisa (IT)
- University of Salerno (IT)
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- University of Ferrara (IT)
- Universitätsklinikum Erlangen (DE)
- Cancer Research Center (US)
- Centro de Investigación del Cáncer (ES)
- Comprehensive Cancer Center Erlangen (DE)
- University of Calabria (IT)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2026-01-05
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c02237
- Primary Topic
- Histone Deacetylase Inhibitors Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00