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

Carullo G, Falbo F, Tudino V, Song J, Fava M, Fontana A, Koch A, Heiß A, Erlenbach-Wünsch K, Panzeca G, Brogi S, Bichicchi A, Saponara S, Fusi F, Vincenzi F, Varani K, Cappello M, Pasquini S, Ramunno A, Pepe G, Butini S, Aiello F, Gemma S, Schneider-Stock R, Campiani G (2026)

Publication Type: Journal article

Publication year: 2026

Journal

Book Volume: 69

Pages Range: 1049-1074

Journal Issue: 2

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.

Authors with CRIS profile

Involved external institutions

Università degli Studi di Salerno Italy (IT) Università degli Studi di Siena (UNISI) / University of Siena Italy (IT) Università della Calabria (UNICAL) Italy (IT) University of Pisa / Università di Pisa (UniPi) Italy (IT) Università degli Studi di Ferrara Italy (IT)

How to cite

APA:

Carullo, G., Falbo, F., Tudino, V., Song, J., Fava, M., Fontana, A.,... Campiani, G. (2026). Targeting Class I Histone Deacetylases Triggers Antitumor Responses in Colorectal Cancer In Vitro and In Vivo. Journal of Medicinal Chemistry, 69(2), 1049-1074. https://doi.org/10.1021/acs.jmedchem.5c02237

MLA:

Carullo, Gabriele, et al. "Targeting Class I Histone Deacetylases Triggers Antitumor Responses in Colorectal Cancer In Vitro and In Vivo." Journal of Medicinal Chemistry 69.2 (2026): 1049-1074.

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