Determination of Slow-Binding HDAC Inhibitor Potency and Subclass Selectivity

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Standard

Determination of Slow-Binding HDAC Inhibitor Potency and Subclass Selectivity. / Moreno-Yruela, Carlos; Olsen, Christian A.

I: ACS Medicinal Chemistry Letters, Bind 13, Nr. 5, 2022, s. 779-785.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt

Harvard

Moreno-Yruela, C & Olsen, CA 2022, 'Determination of Slow-Binding HDAC Inhibitor Potency and Subclass Selectivity', ACS Medicinal Chemistry Letters, bind 13, nr. 5, s. 779-785. https://doi.org/10.1021/acsmedchemlett.1c00702

APA

Moreno-Yruela, C., & Olsen, C. A. (2022). Determination of Slow-Binding HDAC Inhibitor Potency and Subclass Selectivity. ACS Medicinal Chemistry Letters, 13(5), 779-785. https://doi.org/10.1021/acsmedchemlett.1c00702

Vancouver

Moreno-Yruela C, Olsen CA. Determination of Slow-Binding HDAC Inhibitor Potency and Subclass Selectivity. ACS Medicinal Chemistry Letters. 2022;13(5):779-785. https://doi.org/10.1021/acsmedchemlett.1c00702

Author

Moreno-Yruela, Carlos ; Olsen, Christian A. / Determination of Slow-Binding HDAC Inhibitor Potency and Subclass Selectivity. I: ACS Medicinal Chemistry Letters. 2022 ; Bind 13, Nr. 5. s. 779-785.

Bibtex

@article{910f6ad2f54249a2a954d23fb6cd1297,
title = "Determination of Slow-Binding HDAC Inhibitor Potency and Subclass Selectivity",
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.",
keywords = "Enzyme inhibitor, histone deacetylases, continuous assay, slow-binding kinetics, RGFP966",
author = "Carlos Moreno-Yruela and Olsen, {Christian A.}",
year = "2022",
doi = "10.1021/acsmedchemlett.1c00702",
language = "English",
volume = "13",
pages = "779--785",
journal = "ACS Medicinal Chemistry Letters",
issn = "1948-5875",
publisher = "American Chemical Society",
number = "5",

}

RIS

TY - JOUR

T1 - Determination of Slow-Binding HDAC Inhibitor Potency and Subclass Selectivity

AU - Moreno-Yruela, Carlos

AU - Olsen, Christian A.

PY - 2022

Y1 - 2022

N2 - 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.

AB - 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.

KW - Enzyme inhibitor

KW - histone deacetylases

KW - continuous assay

KW - slow-binding kinetics

KW - RGFP966

U2 - 10.1021/acsmedchemlett.1c00702

DO - 10.1021/acsmedchemlett.1c00702

M3 - Journal article

C2 - 35586419

VL - 13

SP - 779

EP - 785

JO - ACS Medicinal Chemistry Letters

JF - ACS Medicinal Chemistry Letters

SN - 1948-5875

IS - 5

ER -

ID: 320395340