2. Academic Validation
  3. Novel pyridine-containing histone deacetylase inhibitors strongly arrest proliferation, induce apoptosis and modulate miRNAs in cancer cells

Novel pyridine-containing histone deacetylase inhibitors strongly arrest proliferation, induce apoptosis and modulate miRNAs in cancer cells

  • Eur J Med Chem. 2022 Dec 15;247:115022. doi: 10.1016/j.ejmech.2022.115022.
Elisabetta Di Bello 1,  Veronica Sian 2,  Giulio Bontempi 3,  Clemens Zwergel 1,  Rossella Fioravanti 1,  Beatrice Noce 1,  Carola Castiello 1,  Stefano Tomassi 4,  Davide Corinti 1,  Daniela Passeri 5,  Roberto Pellicciari 5,  Ciro Mercurio 6,  Mario Varasi 6,  Lucia Altucci 2,  Marco Tripodi 3,  Raffaele Strippoli 7,  Angela Nebbioso 8,  Sergio Valente 9,  Antonello Mai 10
Affiliations

Affiliations

  • 1 Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185, Rome, Italy.
  • 2 Department of Precision Medicine, "Luigi Vanvitelli" University of Campania, Via L. De Crecchio 7, 80138, Naples, Italy.
  • 3 Department of Molecular Medicine, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185, Rome, Italy; Gene Expression Laboratory, National Institute for Infectious Diseases, Lazzaro Spallanzani IRCCS, Via Portuense, 292, 00149, Rome, Italy.
  • 4 Department of Pharmacy, University of Naples "Federico II", Via D. Montesano 49, 80131, Naples, Italy.
  • 5 TES Pharma S.r.l., Via P. Togliatti 20, Corciano, 06073, Perugia, Italy.
  • 6 IFOM ETS, The AIRC Institute of Molecular Oncology, Via Adamello 16, 20139, Milan, Italy.
  • 7 Department of Molecular Medicine, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185, Rome, Italy; Gene Expression Laboratory, National Institute for Infectious Diseases, Lazzaro Spallanzani IRCCS, Via Portuense, 292, 00149, Rome, Italy. Electronic address: raffaele.strippoli@uniroma1.it.
  • 8 Department of Precision Medicine, "Luigi Vanvitelli" University of Campania, Via L. De Crecchio 7, 80138, Naples, Italy. Electronic address: angela.nebbioso@unicampania.it.
  • 9 Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185, Rome, Italy. Electronic address: sergio.valente@uniroma1.it.
  • 10 Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185, Rome, Italy; Pasteur Institute, Cenci-Bolognetti Foundation, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185, Rome, Italy.
PMID: 36549114 DOI: 10.1016/j.ejmech.2022.115022
Abstract

After over 30 years of research, the development of HDAC inhibitors led to five FDA/Chinese FDA-approved drugs and many Others under clinical or preclinical investigation to treat Cancer and non-cancer diseases. Herein, based on our recent development of pyridine-based isomers as HDAC inhibitors, we report a series of novel 5-acylamino-2-pyridylacrylic- and -picolinic hydroxamates and 2'-aminoanilides 5-8 as Anticancer agents. The hydroxamate 5d proved to be quite HDAC3/6-selective exhibiting IC50 values of 80 and 11 nM, respectively, whereas the congener 5e behaved as inhibitor of HDAC1-3, -6, -8, and -10 (class I/IIb-selective inhibitor) at nanomolar level. Compound 5e provided a huge antiproliferative activity (nanomolar IC50 values) against both haematological and solid Cancer cell lines. In leukaemia U937 cells, the hydroxamate 5d and the 2'-aminoanilide 8f induced remarkable cell death after 48 h, with 76% and 100% pre-G1 phase arrest, respectively, showing a stronger effect with respect to SAHA and MS-275 used as reference compounds. In U937 cells, the highest dose- and time-dependent cytodifferentiation was obtained by the 2'-aminoanilide 8d (up to 35% of CD11c positive/propidium iodide negative cells at 5 μM for 48 h). The same 8d and the hydroxamates 5d and 5e were the most effective in inducing p21 protein expression in the same cell line. Mechanistically, 5d, 5e, 8d and 8f increased mRNA expression of p21, Bax and Bak, downregulated cyclin D1 and Bcl-2 and modulated pro- and anti-apoptotic MicroRNAs towards Apoptosis induction. Finally, 5e strongly arrested proliferation in nine different haematological Cancer cell lines, with dual-digit nanomolar potency towards MV4-11, Kasumi-1, and NB4, being more potent than mocetinostat, used as reference drug.

Keywords

Apoptosis; Cancer; HDAC inhibitors; Histone acetylation; Proliferation; miRNAs.

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