Structure-Based Design and Biological Characterization of Selective Histone Deacetylase 8 (HDAC8) Inhibitors with Anti-Neuroblastoma Activity
Abstract
Histone deacetylases (HDACs) are important modulators of epigenetic gene regulation and additionally control the activity of non-histone protein substrates. While for HDACs 1-3 and 6 many potent selective inhibitors have been obtained, for other subtypes much less is known on selective inhibitors and the consequences of their inhibition. The present report describes the development of substituted benzhydroxamic acids as potent and selective HDAC8 inhibitors. Docking studies using available crystal structures have been used for structure-based optimization of this series of compounds. Within this study, we have investigated the role of HDAC8 in the proliferation of cancer cells and optimized hits for potency and selectivity, both in vitro and in cell culture. The combination of structure-based design, synthesis, and in vitro screening to cellular testing resulted in potent and selective HDAC8 inhibitors that showed anti-neuroblastoma activity in cellular testing.
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smHDAC8 crystals can be used to look at inhibitor binding in a crystal lattice-unbiased manner.
“We have previously shown that our smHDAC8 crystals can be used to look at inhibitor binding in a crystal latticeunbiased manner 29, 30, 55-58 .”
From Characterization of Histone Deacetylase 8 (HDAC8) Selective Inhibition Reveals Specific Active Site Structural and Functional Determinants (2018) · cites this paper as [56]
Cites
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- Authors
- Heimburg, T., Kolbinger, F. R., Zeyen, P., Ghazy, E., Herp, D., Schmidtkunz, K., Melesina, J., Shaik, T. B., Erdmann, F., Schmidt, M., Romier, C., Robaa, D., Witt, O., Oehme, I., Jung, M., & Sippl, W.
- Affiliations
- Martin Luther University Halle-Wittenberg (DE)
- German Cancer Research Center (DE)
- University of Freiburg (DE)
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Sippl, Wolfgang
- ORCID
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2017-12-15
- Volume
- 60
- Issue
- 24
- Pages
- 10188-10204
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W2771762430
- Cited by
- 92
- References
- 11
- Citations by year
- 2026: 9 · 2025: 9 · 2024: 15 · 2023: 11 · 2022: 13 · 2021: 12 · 2020: 8 · 2019: 7 · 2018: 8
- FWCI
- 2.79
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (Ju 295/13-1, Oe 542/2-1, Si 846/13-1, Wi 1461-/4-1)
- Deutsche Krebshilfe (112065)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Enzyme function and inhibition
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Keywords
- HDAC8, HDAC8 inhibitors, benzhydroxamic acid, structure-based drug design, neuroblastoma, epigenetic regulation, tumor cell proliferation, inhibitor selectivity, molecular docking
- MeSH terms
- Antineoplastic Agents, Drug Screening Assays, Antitumor, Histone Deacetylases, Humans, Hydroxamic Acids, Neuroblastoma, Repressor Proteins, Structure-Activity Relationship, Biomarkers, Tumor, Drug Design, Gene Expression Regulation, Neoplastic, Cell Line, Tumor, Histone Deacetylase Inhibitors, HEK293 Cells, Molecular Docking Simulation
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