Substituted 2-(2-Aminopyrimidin-4-Yl)Pyridine-4-Carboxylates as Potent Inhibitors of Jumonjic Domain-Containing Histone Demethylases

Roatsch, Martin; Robaa, Dina; Pippel, Martin; Nettleship, Joanne E.; Reddivari, Yamini; Bird, Louise E.; Hoffmann, Inga; Franz, Henriette; Owens, Raymond J.; Schüle, Roland; Flaig, Ralf; Sippl, Wolfgang; Jung, Manfred

doi:10.4155/fmc.15.188

Cited by 17 publications

(12 citation statements)

References 69 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These compounds were generally very potent against KDM4A (compound 3,F igure 1, IC 50 = 0.37 mm), and their cell-permeable prodrugs showeda na ntiproliferative activity against esophageal cancerc ell line (KYSE-150). [23] Finally,v ery recently,c ompound 4 ( Figure 1) was disclosedb yB avetsias et al [24] This compound exhibits an IC 50 of 17 nm against KDM4B and 15 nm against KDM5B, and it is selectivea gainst other JmjC demethylase subfamilies.…”

Section: Introductionmentioning

confidence: 92%

4‐Biphenylalanine‐ and 3‐Phenyltyrosine‐Derived Hydroxamic Acids as Inhibitors of the JumonjiC‐Domain‐Containing Histone Demethylase KDM4A

et al. 2016

Self Cite

View full text Add to dashboard Cite

Overexpression of the histone lysine demethylase KDM4A, which regulates H3K9 and H3K36 methylation states, has been related to the pathology of several human cancers. We found that a previously reported hydroxamate-based histone deacetylase (HDAC) inhibitor (SW55) was also able to weakly inhibit this demethylase with an IC50 value of 25.4 μm. Herein we report the synthesis and biochemical evaluations, with two orthogonal in vitro assays, of a series of derivatives of this lead structure. With extensive chemical modifications on the lead structure, also by exploiting the versatility of the radical arylation with aryldiazonium salts, we were able to increase the potency of the derivatives against KDM4A to the low-micromolar range and, more importantly, to obtain demethylase selectivity with respect to HDACs. Cell-permeable derivatives clearly showed a demethylase-inhibition-dependent antiproliferative effect against HL-60 human promyelocytic leukemia cells.

show abstract

Section: Introductionmentioning

confidence: 92%

4‐Biphenylalanine‐ and 3‐Phenyltyrosine‐Derived Hydroxamic Acids as Inhibitors of the JumonjiC‐Domain‐Containing Histone Demethylase KDM4A

et al. 2016

Self Cite

View full text Add to dashboard Cite

show abstract

“…The study yielded compound 54 ( Figure 48 ) with a K i of 186 nM (IC 50 = 0.37 ± 0.028 μM). 650 However, testing of closely related analogs of this inhibitor against two other demethylases revealed that while the compounds were selective for KDM4A over KDM6B, they were slightly more potent (2-fold) for KDM5A. A cocrystal structure (PDB ID: 5ANQ) and kinetic experiments revealed that these inhibitors were competitive with 2-OG.…”

Section: Histone Demethylasesmentioning

confidence: 99%

Inhibitors of Protein Methyltransferases and Demethylases

2017

View full text Add to dashboard Cite

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.

show abstract

“…14 As JumonjiC KDMs use molecular oxygen as oxidizing agent for the demethylation reaction, a role in cellular oxygen sensing has also been discussed, e. g. for the subtype KDM6A. 15 JmjC histone demethylases have emerged as promising drug targets, 1,[16][17][18][19][20] with inhibitor discovery programs being reported by us [21][22][23][24][25][26][27] and others, [28][29][30][31][32][33][34][35] as recently reviewed. 17,19,[36][37][38][39][40] The majority of reported JmjC KDM inhibitors function by active site metal chelation and competitive displacement of the co-substrate 2OG.…”

mentioning

confidence: 99%

The Clinically Used Iron Chelator Deferasirox Is an Inhibitor of Epigenetic JumonjiC Domain-Containing Histone Demethylases

et al. 2019

Self Cite

View full text Add to dashboard Cite

Supporting Information available: This material is available free of charge via the internet. It includes further enzyme inhibition data (MS), enzyme kinetic analyses, detailed EPR spectroscopic analyses, NMR binding experiments of control compounds, docking structures, as well as further analyses of the cellular effects of deferasirox (cell proliferation, western blots, immunostaining). Additional experimental methods are presented. AUTHOR INFORMATION

show abstract

Substituted 2-(2-Aminopyrimidin-4-Yl)Pyridine-4-Carboxylates as Potent Inhibitors of Jumonjic Domain-Containing Histone Demethylases

Abstract: Virtual screening and rational structural optimization led to a novel scaffold for highly potent and selective JMJD2A inhibitors.

Cited by 17 publications

References 69 publications

4‐Biphenylalanine‐ and 3‐Phenyltyrosine‐Derived Hydroxamic Acids as Inhibitors of the JumonjiC‐Domain‐Containing Histone Demethylase KDM4A

4‐Biphenylalanine‐ and 3‐Phenyltyrosine‐Derived Hydroxamic Acids as Inhibitors of the JumonjiC‐Domain‐Containing Histone Demethylase KDM4A

Inhibitors of Protein Methyltransferases and Demethylases

The Clinically Used Iron Chelator Deferasirox Is an Inhibitor of Epigenetic JumonjiC Domain-Containing Histone Demethylases

Contact Info

Product

Resources

About