Investigations on small molecule inhibitors targeting the histone H3K4 tri-methyllysine binding PHD-finger of JmjC histone demethylases

Abstract

Plant homeodomain (PHD) containing proteins are important epigenetic regulators and are of interest as potential drug targets. Inspired by the amiodarone derivatives reported to inhibit the PHD finger 3 of KDM5A (KDM5A(PHD3)), a set of compounds were synthesised. Amiodarone and its derivatives were observed to weakly disrupt the interactions of a histone H3K4me3 peptide with KDM5A(PHD3). Selected amiodarone derivatives inhibited catalysis of KDM5A, but in a PHD-finger independent manner. Amiodarone derivatives also bind to H3K4me3-binding PHD-fingers from the KDM7 subfamily. Further work is required to develop potent and selective PHD finger inhibitors.

CLP1, a Novel Plant Homeo Domain Protein, Participates in Regulating Cellulase Gene Expression in the Filamentous Fungus Trichoderma reesei

“…Recruitment of nucleosome modifiers such as histone acetyltransferases to specific promoter regions facilitates the activation of a gene packaged within chromatin, by loosening the chromatin structure to uncover binding sites for regulators and for the transcriptional machinery (Mizzen and Allis, 1998; Church and Fleming, 2018). Proteins containing plant homeo domain (PHD) typified with a well-conserved Zn finger motif of the (Cys4)-His-(Cys3) type have been reported to be involved in chromatin-mediated transcription regulation (Aasland et al, 1995; Sanchez and Zhou, 2011; Bhushan et al, 2018). One such PHD finger-containing protein of Saccharomyces cerevisiae , CTI6, has been shown to participate in securing the rapid GAL1 transcriptional activation via acting in concert with the histone acetyltransferase-containing complex SAGA to alleviate Cyc8-Tup1-mediated repression (Papamichos-Chronakis et al, 2002; Han and Emr, 2011).…”

Access to Multifunctionalized Benzofurans by Aryl Nickelation of Alkynes: Efficient Synthesis of the Anti‐Arrhythmic Drug Amiodarone

“…Theb is(hetero)arylated ketone 13 was obtained by the oxidative CÀCb ond cleavage of 3hf. [19] This short and efficient total synthesis of amiodarone from the easily prepared 1h proves the practicality of the developed methodology. [19] This short and efficient total synthesis of amiodarone from the easily prepared 1h proves the practicality of the developed methodology.…”

“…The bis(hetero)arylated ketone 13 was obtained by the oxidative C−C bond cleavage of 3 hf . Subsequent phenol ring iodination and O‐alkylation generated 15 . This short and efficient total synthesis of amiodarone from the easily prepared 1 h proves the practicality of the developed methodology.…”

Identification of ryuvidine as a KDM5A inhibitor

“…These findings have encouraged the development of KDM5 inhibitors 37,38 . Indeed, some compounds that show promise as potential drugs have been reported 39–45 .…”