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Cysteine derivatives as acetyl lysine mimics to inhibit zinc-dependent histone deacetylases for treating cancer.
- Source :
-
European journal of medicinal chemistry [Eur J Med Chem] 2021 Dec 05; Vol. 225, pp. 113799. Date of Electronic Publication: 2021 Aug 27. - Publication Year :
- 2021
-
Abstract
- Zinc-dependent histone deacetylases (HDACs) are important epigenetic regulators that have become important drug targets for treating cancer. Although five HDAC inhibitors have been approved for treating several cancers, there is still a huge demand on discovering new HDAC inhibitors to explore the therapeutic potentials for treating solid tumor cancers. Substrate mimics are a powerful rational design approach for the development of potent inhibitors. Here we describe the rational design, synthesis, biological evaluation, molecular docking and in vivo efficacy study of a class of HDAC inhibitors using N <superscript>ε</superscript> -acetyl lysine mimics that are derived from cysteine. As a result, compounds 7a, 9b and 13d demonstrated pan-HDAC inhibition and broad cytotoxicity against several cancer cell lines, comparable to the approved HDAC inhibitor SAHA. Furthermore, 13d significantly inhibited tumor growth in a A549 xenograft mice model without any obvious weight loss, supporting that the cysteine-derived acetyl lysine mimics are promising HDAC inhibitors with therapeutic potentials for treating cancer.<br />Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)
- Subjects :
- Animals
Antineoplastic Agents chemical synthesis
Antineoplastic Agents chemistry
Apoptosis drug effects
Cell Cycle drug effects
Cell Line, Tumor
Cell Proliferation drug effects
Cysteine chemical synthesis
Cysteine chemistry
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Female
Histone Deacetylase Inhibitors chemical synthesis
Histone Deacetylase Inhibitors chemistry
Humans
Lysine chemistry
Mice
Mice, Inbred BALB C
Mice, Nude
Molecular Docking Simulation
Molecular Structure
Neoplasms, Experimental drug therapy
Neoplasms, Experimental metabolism
Neoplasms, Experimental pathology
Structure-Activity Relationship
Antineoplastic Agents pharmacology
Cysteine pharmacology
Histone Deacetylase Inhibitors pharmacology
Histone Deacetylases metabolism
Lysine pharmacology
Zinc metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1768-3254
- Volume :
- 225
- Database :
- MEDLINE
- Journal :
- European journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 34500130
- Full Text :
- https://doi.org/10.1016/j.ejmech.2021.113799