Potent and Selective KDM5 Inhibitor Stops Cellular Demethylation of H3K4me3 at Transcription Start Sites and Proliferation of MM1S Myeloma Cells

Abstract

SummaryMethylation of lysine residues on histone tail is a dynamic epigenetic modification that plays a key role in chromatin structure and gene regulation. Members of the KDM5 (also known as JARID1) sub-family are 2-oxoglutarate (2-OG) and Fe2+-dependent oxygenases acting as histone 3 lysine 4 trimethyl (H3K4me3) demethylases, regulating proliferation, stem cell self-renewal, and differentiation. Here we present the characterization of KDOAM-25, an inhibitor of KDM5 enzymes. KDOAM-25 shows biochemical half maximal inhibitory concentration values of <100 nM for KDM5A-D in vitro, high selectivity toward other 2-OG oxygenases sub-families, and no off-target activity on a panel of 55 receptors and enzymes. In human cell assay systems, KDOAM-25 has a half maximal effective concentration of ∼50 μM and good selectivity toward other demethylases. KDM5B is overexpressed in multiple myeloma and negatively correlated with the overall survival. Multiple myeloma MM1S cells treated with KDOAM-25 show increased global H3K4 methylation at transcriptional start sites and impaired proliferation.

KDM5 Histone Demethylase Activity Links Cellular Transcriptomic Heterogeneity to Therapeutic Resistance

“…Compounds KDM5-C49 and KDM5-C70 were synthesized following the reported procedure (Tumber et al, 2017), and also sourced from commercial vendors. All the chemical reagents and anhydrous solvents were purchased from Sigma-Aldrich and Strem.…”

Studies on the Interaction of the Histone Demethylase KDM5B with Tricarboxylic Acid Cycle Intermediates

“…Cells with overexpressed KDM5B were treated with different concentrations of the TCA cycle-related pro-drug esters (previously established as cell permeable in other cell-based studies) [28] , [51] , [52] , [53] , [54] for 24 h, the H3K4me 3 levels were then analyzed in the transfected cells. The reported KDM5B inhibitor KDOAM-25 ((2)-((((2)-(((2)-(dimethylamino)ethyl)(ethyl)amino)-(2)-oxoethyl)amino)methyl)isonicotinamide) was used as a positive control for inhibition [50] , [55] . Comparison of cells transfected with WT KDM5B or KDM5B Mut expressing vectors showed the expected decrease in H3K4me 3 levels in the WT transfected cells ( Fig.…”

Epigenetic markers in basal cell carcinoma: universal themes in oncogenesis and tumor stratification? - a short report

“…The application of JARID1B and NSD2 inhibitors in animal models may reveal whether their antagonism promotes or inhibits BCC growth. JARID1B and NSD2 inhibitors are currently in clinical development for multiple myeloma and other cancers [5, 7, 15, 16]. Understanding their biology in the context of BCC may facilitate the optimization of their therapeutic potential.…”