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Cited by 93Histone Deacetylase Inhibitors ResearchSynthesis and biological activityEnzyme function and inhibition

Class I HDAC Inhibitors Display Different Antitumor Mechanism in Leukemia and Prostatic Cancer Cells Depending on Their p53 Status

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Li, Xiaoyang, Peterson, Yuri K., Inks, Elizabeth S., Himes, Richard A., Li, Jiaying, Zhang, Yingjie, Kong, Xiujie, Chou, C. James·2018·Journal of Medicinal Chemistry
DOI 10.1021/acs.jmedchem.8b00136PMC PMC5908721
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Abstract

Previously, we designed and synthesized a series of o -aminobenzamide-based histone deacetylase (HDAC) inhibitors, among which the representative compound 11a exhibited potent inhibitory activity against class I HDACs. In this study, we report the development of more potent hydrazide-based class I selective HDAC inhibitors using 11a as a lead. Representative compound 13b showed a mixed, slow, and tight binding inhibition mechanism for HDAC1, 2, and 3. The most potent compound 13e exhibited low nanomolar IC 50 s toward HDAC1, 2, and 3 and could down-regulate HDAC6 in acute myeloid leukemia MV4-11 cells. The EC 50 of 13e against MV4-11 cells was 34.7 nM, which is 26 times lower than its parent compound 11a . In vitro responses to 13e vary significantly and interestingly based on cell type: in p53 wild-type MV4-11 cells, 13e induced cell death via apoptosis and G1/S cell cycle arrest, which is likely mediated by a p53-dependent pathway, while in p53-null PC-3 cells, 13e caused G2/M arrest and inhibited cell proliferation without inducing caspase-3-dependent apoptosis.

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Authors
Li, X., Peterson, Y. K., Inks, E. S., Himes, R. A., Li, J., Zhang, Y., Kong, X., & Chou, C. J.
Affiliations
  • Medical University of South Carolina (US)
  • Lydex Pharmaceuticals, 330 Concord Street, Unit 6A, Charleston, South Carolina 29401, United States
  • Shandong University (CN)
Corresponding author
Chou, C. James
ORCID
Venue
Journal of Medicinal Chemistry
Publisher
American Chemical Society (ACS)
Published
2018-03-02
Volume
61
Issue
6
Pages
2589-2603
ISSN
  • 0022-2623 (ISSN-L)
  • 1520-4804
DOI
10.1021/acs.jmedchem.8b00136
PMC
PMC5908721
OpenAlex
W2792072457
Cited by
93
References
7
Citations by year
2026: 5 · 2025: 14 · 2024: 15 · 2023: 14 · 2022: 12 · 2021: 15 · 2020: 8 · 2019: 6 · 2018: 4
FWCI
3.38
Type
journal article
Language
en
Open access
Locations
  • Journal of Medicinal Chemistry (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Cancer Institute (CA163452)
  • National Institute of General Medical Sciences (P20GM103542)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
  • Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Enzyme function and inhibition
Keywords
class I HDAC inhibitors, histone deacetylase inhibitors, HDAC1, HDAC2, HDAC3, HDAC6, acute myeloid leukemia, prostate cancer, p53 status, apoptosis, G1/S cell cycle arrest, G2/M cell cycle arrest, caspase-3, anticancer mechanism, MV4-11 cells, PC-3 cells
MeSH terms
PC-3 Cells, Antineoplastic Agents, Humans, Kinetics, Leukemia, Male, Prostatic Neoplasms, Structure-Activity Relationship, Genes, p53, Apoptosis, CD13 Antigens, Cell Line, Tumor, Caspase 3, Histone Deacetylase 1, Histone Deacetylase Inhibitors, HEK293 Cells, Cell Cycle Checkpoints, Matrix Metalloproteinase Inhibitors, Molecular Docking Simulation

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