Discovery of Histone Demethylase Inhibitors

Hauser, Alexander‐Thomas; Roatsch, Martin; Schulz-Fincke, Johannes; Robaa, Dina; Sippl, Wolfgang; Jung, Manfred

doi:10.1016/b978-0-12-801080-8.00018-1

Cited by 5 publications

(6 citation statements)

References 107 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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. [36][37][38][39] Very recently, covalent KDM5 5 inhibitors 41,42 and inhibitors of both the lysyl-and arginyl-demethylase activities 43 have also been reported.…”

mentioning

confidence: 99%

“…JmjC histone demethylases have emerged as promising drug targets, ,− with inhibitor discovery programs being reported by us − and others, − as recently reviewed. ,,− A majority of reported JmjC KDM inhibitors function by active site metal chelation and competitive displacement of the co-substrate 2OG. − Very recently, covalent KDM5 inhibitors , and inhibitors of both the lysyl- and arginyl-demethylase activities have also been reported.…”

mentioning

confidence: 99%

See 1 more Smart Citation

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

mentioning

confidence: 99%

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

show abstract

“…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. [36][37][38][39] Very recently, covalent KDM5 inhibitors 41,42 and inhibitors of both the lysyl-and arginyl-demethylase activities 43 have also been reported.…”

Section: Abstract Epigenetics • Histone Demethylase • Inhibitor • Off-target • Clinically Used Drugs • Deferasirox •mentioning

confidence: 99%

“…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. [36][37][38][39] Very recently, covalent KDM5 inhibitors 41,42 and inhibitors of both the lysyl-and arginyl-demethylase activities 43 have also been reported.…”

Section: Abstract Epigenetics • Histone Demethylase • Inhibitor • Off-target • Clinically Used Drugs • Deferasirox •mentioning

confidence: 99%

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

Jung¹,

Roatsch²,

Hoffmann³

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

Fe(II)- and 2-oxoglutarate (2OG)-dependent JumonjiC domain-containing histone demethylases (JmjC KDMs) are epigenetic eraser enzymes involved in the regulation of gene expression and are emerging drug targets in oncology. We screened a set of clinically used iron chelators and report that they potently inhibit JMJD2A (KDM4A) in vitro. Mode of action investigations revealed that one compound, deferasirox, is a bona fide active site-binding inhibitor as shown by kinetic and spectroscopic studies. Synthesis of derivatives with improved cell permeability resulted in significant upregulation of histone trimethylation and potent cancer cell growth inhibition. Deferasirox was also found to similarly inhibit human 2OG-dependent hypoxia inducible factor prolyl hydroxylase activity. Therapeutic effects of clinically used deferasirox may thus involve transcriptional regulation through 2OG oxygenase inhibition. Deferasirox may provide a useful starting point for the development of novel anticancer drugs targeting 2OG oxygenases and a valuable tool compound for investigations of KDM function.<br>

show abstract

“…A number of inhibitors for JmjC histone demethylases have been published to date, of which a selection is summarized in Figure 1. Advances in inhibitor design have recently been reviewed [17,[30][31][32][33][34]. Among the first published inhibitors were metal ion chelators, which bind to the ferrous ion center and competitively displace the cosubstrate 2-oxoglutarate 1a, such as N-oxalylglycine 1b with proven potency against the closely related subtype JMJD2E [35].…”

mentioning

confidence: 99%

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

et al. 2016

Self Cite

View full text Add to dashboard Cite

show abstract

Discovery of Histone Demethylase Inhibitors

Cited by 5 publications

References 107 publications

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

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

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

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

Contact Info

Product

Resources

About