RGFP966

Inhibitor of HDAC3

Structure

Information

Protein target names: HDAC3

Mechanism of action: Inhibitor

In Vitro Validations

Uniprot ID: O15379
Target Class: Epigenetic
Target SubClass: HDAC
Potency: IC50
Potency Value: 0.08 uM
Potency Assay: Substrate-dependent biochemical assays (Reaction Biology). Extensive biochemical characterization has been published on a related compound 106 (Chem Biol. publication): HDAD3 Ki= 14 nM; IC50 with recombinant HDAC3=0.79 uM.
PDB ID for probe-target interaction (3D structure): --
Structure-activity relationship: Yes, several compounds on the pimelic diphenylamide scaffold have been reported with variable activity and specificity for HDAC proteins (see PLoS One report).
Target aliases:
Histone deacetylase 3, HDAC3, HDAC3_HUMAN, HD3, SM ...

In Cell Validations

In Vivo Data

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SERP ratings and comments


SERP Ratings

In Cell Rating
In Model Organisms

(last updated: 26 Apr 2017 )

SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

This is an N-(o-amino-phenyl)carboxamide HDAC3-selective inhibitor with an IC50 of 80 nM and 'no effective inhibition of other HDACs' at concentrations up to 15 uM utilizing a substrate-dependent biochemical assay with recombinant human protein (Malvaez et al PNAS 2013; 110: 2647-2652 - primary data not shown). However, functional data suggests possible inhibition of other class I HDACs at concentrations >1 uM (Matthews et al Blood 2015; 126: 2392-2403) - please refer to 'cellular concentration notes'. For in vivo dosing, 10 mg/kg delivered subcutaneously achieves a maximum tissue concentration (brain) in mice of 3.15 uM at 30 minutes, with concentrations exceeding the IC50 for HDAC3 for at least 2 hours in this tissue.

(last updated: 31 May 2017 )

SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

RGFP966 has been demonstrated to have selective activity for HDAC3 in biochemical assays over most other HDAC enzymes. In cells, Matthews et al., (Blood, 2015) observed that RGFP966 treatment phenocopied genetic HDAC3 perturbation up to ~1,000 nM. Thus, cellular studies using RGFP966 for selective pharmacologic HDAC3 perturbation should be limited to concentrations <1,000 nM. In mouse and rat models, RGFP966 has been observed to be brain-penetrant when dosed subcutaneously. When used for in vivo studies, care should be taken to pair phenotypic observations from genetic-perturbation studies of HDACs in order to have higher confidence in HDAC3-selective effects.

(last updated: 12 Jun 2017 )

Portal Comments

According to the latest paper from Olsen’s Lab (DOI:10.1021/acsmedchemlett.1c00702) RGFP966 has only a marginal preference for HDAC3 vs HDAC1 and 2, hence it shouldn’t be considered as a selective probe for HDAC3.

(last updated: 25 May 2022)