Determination of Slow-Binding HDAC Inhibitor Potency and Subclass Selectivity
Research output: Contribution to journal › Journal article › Research › peer-review
Standard
Determination of Slow-Binding HDAC Inhibitor Potency and Subclass Selectivity. / Moreno-Yruela, Carlos; Olsen, Christian A.
In: ACS Medicinal Chemistry Letters, Vol. 13, No. 5, 2022, p. 779-785.Research output: Contribution to journal › Journal article › Research › peer-review
Harvard
APA
Vancouver
Author
Bibtex
}
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