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Determination of Slow-binding HDAC Inhibitor Potency and Subclass Selectivity
Open accessPreprint — published as 10.1021/acsmedchemlett.1c00702
Abstract
Histone deacetylases (HDACs) 1-3 regulate chromatin structure and gene expression. These three enzymes are targets for cancer chemotherapy and have been studied for the treatment of immune disorders and neurodegeneration, but there is a lack of selective pharmacological tool compounds to unravel their individual roles. Potent inhibitors of HDACs 1-3 often display slow-binding kinetics, which causes a delay in inhibitor-enzyme equilibration and may affect assay readout. Here we compare the potencies and selectivities of slow-binding inhibitors measured by discontinuous and continuous assays. We find that entinostat, a clinical candidate, inhibits HDACs 1-3 by a two-step slow-binding mechanism with lower potencies than previously reported. In addition, we show that RGFP966, commercialized as an HDAC3-selective probe, is a slow-binding inhibitor with inhibitor constants of 57, 31, and 13 nM against HDACs 1-3, respectively. These data highlight the need for thorough kinetic investigation in the development of selective HDAC probes.
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“Hence, 2-amino anilides tend to have significantly longer residence times in the protein than hydroxamic acids and this unlocks unique binding profiles of the 2-amino anilide inhibitors [17, 19, 20].”
From Medicinal chemistry advances in targeting class I histone deacetylases (2023) · cites this paper as [17]
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“However, because of the intra- to inter-molecular conversion, 2-amino anilides have been reported to exhibit slow-binding kinetics with HDACs 1–3.”
From Medicinal chemistry advances in targeting class I histone deacetylases (2023) · cites this paper as [17]
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Medicinal chemistry advances in targeting class I histone deacetylases
Abdallah, D. I., de Araujo, E. D., Patel, N. H., Hasan, L. S., Moriggl, R., Krämer, O. H., & Gunning, P. T. (2023) · Exploration of Targeted Anti-tumor Therapy · doi:10.37349/etat.2023.00166 · Cited by 17
“For example, a selective HDAC3 inhibitor, RGFP966, has been shown to exhibit a time-dependent reduction in half maximal inhibitory concentration (IC50) with longer pre-incubation times [18].”
BackgroundInfluential
Metadata
- Authors
- Moreno-Yruela, C., & Olsen, C. A.
- Affiliations
- University of Copenhagen (DK)
- Corresponding author
- Olsen, Christian A.
- Venue
- ACS Medicinal Chemistry Letters
- Publisher
- openRxiv
- Published
- 2021-12-18
- Volume
- 13
- Issue
- 5
- Pages
- 779-785
- ISSN
- 1948-5875 (ISSN-L)
- PMC
- PMC9109163
- OpenAlex
- W4221105689
- Cited by
- 41
- References
- 1
- Citations by year
- 2026: 5 · 2025: 11 · 2024: 11 · 2023: 8 · 2022: 6
- FWCI
- 2.94
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- ACS Medicinal Chemistry Letters (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
- Funders
- European Commission (HORIZON2020)
- H2020 European Research Council (ERC-CoG-725172?SIRFUNCT)
- 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 (medical) › Cholinesterase and Neurodegenerative Diseases
- Keywords
- histone deacetylase, histone deacetylase inhibitors, entinostat, RGFP966, HDAC1, HDAC2, HDAC3, inhibitor potency, enzyme selectivity, inhibition constant
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