2. Academic Validation
  3. N-(2-Aminophenyl)-benzamide Inhibitors of Class I HDAC Enzymes with Antiproliferative and Antifibrotic Activity

N-(2-Aminophenyl)-benzamide Inhibitors of Class I HDAC Enzymes with Antiproliferative and Antifibrotic Activity

  • J Med Chem. 2023 Oct 26;66(20):14357-14376. doi: 10.1021/acs.jmedchem.3c01422.
Dimitrios Triantafyllos Gerokonstantis 1 2,  Christiana Mantzourani 1 2,  Dimitrios Gkikas 3,  Kai-Chen Wu 4,  Huy N Hoang 4,  Ierasia Triandafillidi 1 2,  Ilianna Barbayianni 5,  Paraskevi Kanellopoulou 5,  Alexandros C Kokotos 3,  Panagiota Moutevelis-Minakakis 1 2,  Vassilis Aidinis 5,  Panagiotis K Politis 3 6,  David P Fairlie 4,  George Kokotos 1 2
Affiliations

Affiliations

  • 1 Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis, Athens 15771, Greece.
  • 2 Center of Excellence for Drug Design and Discovery, National and Kapodistrian University of Athens, Panepistimiopolis, Athens 15771, Greece.
  • 3 Center of Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens 11527, Greece.
  • 4 Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia.
  • 5 Institute for Fundamental Biomedical Research, Biomedical Sciences Research Center "Alexander Fleming", Athens 16672, Greece.
  • 6 School of Medicine, European University Cyprus, Nicosia 1516, Cyprus.
PMID: 37795958 DOI: 10.1021/acs.jmedchem.3c01422
Abstract

Inhibitors of histone deacetylases (HDACs) have received special attention as novel Anticancer agents. Among various types of synthetic inhibitors, benzamides constitute an important class, and one is an approved drug (chidamide). Here, we present a novel class of HDAC inhibitors containing the N-(2-aminophenyl)-benzamide functionality as the zinc-binding group linked to various cap groups, including the Amino acids pyroglutamic acid and proline. We have identified benzamides that inhibit HADC1 and HDAC2 at nanomolar concentrations, with antiproliferative activity at micromolar concentrations against A549 and SF268 Cancer cell lines. Docking studies shed LIGHT on the mode of binding of benzamide inhibitors to HDAC1, whereas cellular analysis revealed downregulated expression of EGFR mRNA and protein. Two benzamides were investigated in a mouse model of bleomycin-induced pulmonary fibrosis, and both showed efficacy on a preventative dosing schedule. N-(2-Aminophenyl)-benzamide inhibitors of class I HDACs might lead to new approaches for treating fibrotic disorders.

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