Uracil- and Pyridine-Containing HDAC Inhibitors Displayed Cytotoxicity in Colorectal and Glioblastoma Cancer Stem Cells

Francesco Fiorentino; Emanuele Fabbrizi; Alessia Raucci; Beatrice Noce; Rossella Fioravanti; Sergio Valente; Chantal Paolini; Ruggero De Maria; Christian Steinkühler; Paola Gallinari; Dante Rotili; Antonello Mai

doi:10.1002/cmdc.202300655

Uracil- and Pyridine-Containing HDAC Inhibitors Displayed Cytotoxicity in Colorectal and Glioblastoma Cancer Stem Cells

ChemMedChem. 2024 Mar 26:e202300655. doi: 10.1002/cmdc.202300655. Online ahead of print.

Authors

Affiliations

¹ Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le Aldo, Moro n. 5, 00185, Rome, Italy.
² IRBM S.p.A., Via Pontina km 30.600, 00071, Pomezia, Rome, Italy.
³ Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168, Rome, Italy.
⁴ Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168, Rome, Italy.
⁵ Research and Development, Italfarmaco Group, Via dei Lavoratori 54, 20092, Cinisello Balsamo, Italy.
⁶ Exiris S.r.l., Tecnopolo Castel, Romano, Via Castel Romano 100, 00128, Rome, Italy.
⁷ Pasteur Institute, Cenci-Bolognetti Foundation, Sapienza University of Rome, P. de Aldo Moro n. 5, 00185, Rome, Italy.

PMID: 38529661
DOI: 10.1002/cmdc.202300655

Abstract

Cancer stem cells (CSCs) are a niche of highly tumorigenic cells featuring self-renewal, activation of pluripotency genes, multidrug resistance, and ability to cause cancer relapse. Seven HDACi (1-7), showing either hydroxamate or 2'-aminoanilide function, were tested in colorectal cancer (CRC) and glioblastoma multiforme (GBM) CSCs to determine their effects on cell proliferation, H3 acetylation levels and in-cell HDAC activity. Two uracil-based hydroxamates, 5 and 6, which differ in substitution at C5 and C6 positions of the pyrimidine ring, exhibited the greatest cytotoxicity in GBM (5) and CRC (6) CSCs, followed by the pyridine-hydroxamate 2, with 2- to 6-fold higher potency than the positive control SAHA. Finally, increased H3 acetylation as well as HDAC inhibition directly in cells by selected 2'-aminoanilide 4 and hydroxamate 5 confirmed target engagement. Further investigation will be conducted into the broad-spectrum anticancer properties of the most potent derivatives and their effects in combination with approved, conventional anticancer drugs.

Keywords: Epigenetics; HDAC inhibitors; cancer stem cells; colorectal cancer; glioblastoma multiforme.

Abstract

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