Design and Synthesis of Pyridone-Containing 3,4-Dihydroisoquinoline-1(2<i>H</i>)-ones as a Novel Class of Enhancer of Zeste Homolog 2 (EZH2) Inhibitors

Kung, Pei‐Pei; Rui, Eugene; Bergqvist, Simon; Bingham, Patrick; Braganza, John; Collins, Michael R.; Cui, Mei; Diehl, Wade; Dinh, Dac M.; Fan, Connie; Fantin, Valeria R.; Gukasyan, Hovhannes J.; Hu, Wenyue; Huang, Buwen; Kephart, Susan E.; Krivacic, Cody; Kumpf, Robert A.; Li, Gary; Maegley, Karen A.; McAlpine, Indrawan; Nguyen, Lisa; Ninkovic, Sacha; Ornelas, Martha A.; Ryskin, Michael; Scales, Stephanie; Sutton, Scott C.; Tatlock, John; Verhelle, Dominique; Wang, Fen; Wells, Peter A.; Wythes, Martin; Yamazaki, Shinji; Yip, Brian; Xiang, Yu; Zehnder, Luke R.; Zhang, Weiguo; Rollins, Robert A.; Edwards, Martin P.

doi:10.1021/acs.jmedchem.6b00515

Cited by 55 publications

(53 citation statements)

References 45 publications

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“…[23] In addition, very recently, new series of pyridone containing inhibitors, which led to the discovery of highly potent EZH2 inhibitor 1 (Figure 2) was reported. [24] Compound 1 displayed cellular potencies in cells that are comparable to previously reported EZH2 inhibitors. It is important to note that EPZ-6438, GSK126 and CPI-1205 are advanced into human clinical trials.…”

Section: Inhibitors Of H3k9 and H3k27 Methyltransferasessupporting

confidence: 67%

Recent progress in developing selective inhibitors of protein methyltransferases

Kaniskan

Jin

2017

Current Opinion in Chemical Biology

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Mounting evidence suggests that protein methyltrans•ferases (PMTs), which catalyze methylation of histone as well as non-histone •proteins, play aa crucial role in diverse biological pathways and human• diseases. In particular, PMTs have been recognized as major players in •regulating gene expression and chromatin state. There has been an increasingly growing• interest in these enzymes as potential therapeutic targets and over the past two years tremendous progress has been made in the discovery of selective, small molecule inhibitors of protein lysine and arginine methyltransferases. Inhibitors of PMTs have been used extensively in oncology studies as tool compounds, and inhibitors of EZH2, DOT1L and PRMT5 are currently in clinical trials.

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Section: Inhibitors Of H3k9 and H3k27 Methyltransferasessupporting

confidence: 67%

Recent progress in developing selective inhibitors of protein methyltransferases

Kaniskan

Jin

2017

Current Opinion in Chemical Biology

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“…Although Ezh2 is essential for embryonic development and tissue maintenance in zebrafish, maternal load of Ezh2 mRNA is probably sufficient to add H3K27me3 mark to the chromatin in embryos as described previously in zygotic ezh2 mutants [37,42]. Ezh2i will block the SET domain of specifically Ezh1/2 proteins and thereby inhibit the catalytic function to add the H3K27me3 mark on the chromatin [43]. Indeed, when we map the ATAC DE peaks to H3K27me3 loci, we see a substantial over-representation at these locations.…”

Section: Discussionmentioning

confidence: 83%

“…We investigated the effect of inhibition of the histone methyl transferase (HMT) activity of enhancer of zeste proteins on zebrafish development with focus on lipid accumulation, and chromatin accessibility due to reduced H3K27me3 levels. Therefore, we exposed zebrafish embryos to the Ezh inhibitor PF-06726304 acetate [25], and measured changes on chromatin structure by the assay for transposase-accessible chromatin sequencing (ATAC-seq), just after zygotic genome activation (ZGA) at 50% epiboly.…”

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confidence: 99%

Inhibition of methyltransferase activity of enhancer of zeste 2 leads to enhanced lipid accumulation and altered chromatin status in zebrafish

Broeder

Ballangby

Kamminga

et al. 2020

Epigenetics & Chromatin

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Background: Recent studies indicate that exposure to environmental chemicals may increase susceptibility to developing metabolic diseases. This susceptibility may in part be caused by changes to the epigenetic landscape which consequently affect gene expression and lead to changes in lipid metabolism. The epigenetic modifier enhancer of zeste 2 (Ezh2) is a histone H3K27 methyltransferase implicated to play a role in lipid metabolism and adipogenesis. In this study, we used the zebrafish (Danio rerio) to investigate the role of Ezh2 on lipid metabolism and chromatin status following developmental exposure to the Ezh1/2 inhibitor PF-06726304 acetate. We used the environmental chemical tributyltin (TBT) as a positive control, as this chemical is known to act on lipid metabolism via EZH-mediated pathways in mammals. Results:Zebrafish embryos (0-5 days post-fertilization, dpf ) exposed to non-toxic concentrations of PF-06726304 acetate (5 μM) and TBT (1 nM) exhibited increased lipid accumulation. Changes in chromatin were analyzed by the assay for transposase-accessible chromatin sequencing (ATAC-seq) at 50% epiboly (5.5 hpf ). We observed 349 altered chromatin regions, predominantly located at H3K27me3 loci and mostly more open chromatin in the exposed samples. Genes associated to these loci were linked to metabolic pathways. In addition, a selection of genes involved in lipid homeostasis, adipogenesis and genes specifically targeted by PF-06726304 acetate via altered chromatin accessibility were differentially expressed after TBT and PF-06726304 acetate exposure at 5 dpf, but not at 50% epiboly stage. One gene, cebpa, did not show a change in chromatin, but did show a change in gene expression at 5 dpf. Interestingly, underlying H3K27me3 marks were significantly decreased at this locus at 50% epiboly. Conclusions:Here, we show for the first time the applicability of ATAC-seq as a tool to investigate toxicological responses in zebrafish. Our analysis indicates that Ezh2 inhibition leads to a partial primed state of chromatin linked to metabolic pathways which results in gene expression changes later in development, leading to enhanced lipid accumulation. Although ATAC-seq seems promising, our in-depth assessment of the cebpa locus indicates that we need to consider underlying epigenetic marks as well.

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“… 139 Very recently, Kung and co-workers reported the design and synthesis of this new series of pyridone inhibitors, which led to the discovery of compound 2 ( Figure 6 ). 142 Compound 2 is a potent EZH2 inhibitor with an IC 50 of <5 nM and a K i of 0.7 nM in biochemical assays. It exhibited cellular potencies in KARPAS-422 cells that are comparable to previously reported EZH2 inhibitors.…”

Section: Protein Methyltransferasesmentioning

confidence: 99%

Inhibitors of Protein Methyltransferases and Demethylases

2017

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Post-translational modifications of histones by protein methyltransferases (PMTs) and histone demethylases (KDMs) play an important role in the regulation of gene expression and transcription and are implicated in cancer and many other diseases. Many of these enzymes also target various nonhistone proteins impacting numerous crucial biological pathways. Given their key biological functions and implications in human diseases, there has been a growing interest in assessing these enzymes as potential therapeutic targets. Consequently, discovering and developing inhibitors of these enzymes has become a very active and fast-growing research area over the past decade. In this review, we cover the discovery, characterization, and biological application of inhibitors of PMTs and KDMs with emphasis on key advancements in the field. We also discuss challenges, opportunities, and future directions in this emerging, exciting research field.

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Design and Synthesis of Pyridone-Containing 3,4-Dihydroisoquinoline-1(2H)-ones as a Novel Class of Enhancer of Zeste Homolog 2 (EZH2) Inhibitors

Cited by 55 publications

References 45 publications

Recent progress in developing selective inhibitors of protein methyltransferases

Recent progress in developing selective inhibitors of protein methyltransferases

Inhibition of methyltransferase activity of enhancer of zeste 2 leads to enhanced lipid accumulation and altered chromatin status in zebrafish

Inhibitors of Protein Methyltransferases and Demethylases

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