Human HDAC isoform selectivity achieved via exploitation of the acetate release channel with structurally unique small molecule inhibitors
Abstract
Herein we report the discovery of a family of novel yet simple, amino-acid derived class I HDAC inhibitors that demonstrate isoform selectivity via access to the internal acetate release channel. Isoform selectivity criteria is discussed on the basis of X-ray crystallography and molecular modeling of these novel inhibitors bound to HDAC8, potentially revealing insights into the mechanism of enzymatic function through novel structural features revealed at the atomic level.
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Benzamides face a more difficult path to the observed binding mode, with two plausible binding trajectories: via an acetyl release and disposal channel or via the hydrophobic tube, settling into a rearranged foot pocket before forming the zinc complex.
“The benzamides face a more difficult path to the observed binding mode, with two plausible binding trajectories. The ligand could enter via an acetyl release and disposal channel (7, 24, 33, 42) or via the hydrophobic tube, settling into a rearranged foot pocket before forming the zinc complex, which locks the inhibitor in place.”
From Histone Deacetylase (HDAC) Inhibitor Kinetic Rate Constants Correlate with Cellular Histone Acetylation but Not Transcription and Cell Viability (2013) · cites this paper as [42]
In HDAC8, the presence of a tryptophan limits the available space in the foot pocket.
“In HDAC8, the presence of a tryptophan limits the available space in the foot pocket.”
From HDACs and the epigenetic plasticity of cancer cells: target the complexity (2022) · cites this paper as Whitehead et al., 2011
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- Authors
- Whitehead, L., Dobler, M. R., Radetich, B., Zhu, Y., Atadja, P. W., Claiborne, T., Grob, J. E., McRiner, A., Pancost, M. R., Patnaik, A., Shao, W., Shultz, M., Tichkule, R., Tommasi, R. A., Vash, B., Wang, P., & Stams, T.
- Corresponding author
- Whitehead, Lewis
- Venue
- Bioorganic & Medicinal Chemistry
- Publisher
- Elsevier BV
- Published
- 2011-08
- Volume
- 19
- Issue
- 15
- Pages
- 4626-4634
- ISSN
- 0968-0896 (ISSN-L)
- OpenAlex
- W2019219956
- Cited by
- 164
- References
- 45
- Citations by year
- 2026: 11 · 2025: 11 · 2024: 9 · 2023: 8 · 2022: 9 · 2021: 12 · 2020: 12 · 2019: 14 · 2018: 20 · 2017: 12 · 2016: 6 · 2015: 12 · 2014: 7 · 2013: 6 · 2012: 12
- FWCI
- 4.15
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Bioorganic & Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- 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
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Keywords
- histone deacetylase inhibitors, class I HDACs, isoform selectivity, HDAC8, small molecule inhibitors, enzyme crystal structure, inhibitor binding mechanism
- MeSH terms
- Amino Acids, Histone Deacetylases, Humans, Models, Molecular, Drug Design, Crystallography, X-Ray, Acetic Acid, Protein Isoforms, Histone Deacetylase Inhibitors
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