Identification of ortho-hydroxy anilide as a novel scaffold for lysine demethylase 5 inhibitors

Jaikhan, Pattaporn; Buranrat, Benjaporn; Itoh, Yukihiro; Chotitumnavee, Jiranan; Kurohara, Takashi; Suzuki, Takayoshi

doi:10.1016/j.bmcl.2019.03.028

Cited by 6 publications

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“…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.…”

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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.…”

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

et al. 2019

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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

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

et al. 2019

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“…123,124) The other class is a family of Fe(II)/αketoglutarate (αKG)-dependent oxidases (KDM2-8). 125) So far, we have identified LSD1, 32,35,[126][127][128] KDM2/7, 129) and KDM5 31,[130][131][132] inhibitors by LBDD, SBDD, and strategic chemistry approaches. In this section, we discuss the discovery of LSD1 inhibitors based on SBDD, LBDD, and enzyme catalytic mechanism.…”

Section: Lysine Methylation Modulators and Their Applicationmentioning

confidence: 99%

Drug Discovery Researches on Modulators of Lysine-Modifying Enzymes Based on Strategic Chemistry Approaches

Itoh

2020

CHEMICAL & PHARMACEUTICAL BULLETIN

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Enzymatic and post-translational modifications (PTMs) such as ubiquitination, acetylation, and methylation occur at lysine residues. The PTMs play critical roles in the regulation of the protein functions, and thus, various cellular processes. In addition, aberrations of the PTMs are associated with various diseases, such as cancer and neurodegenerative disorders. Therefore, we hypothesized that modulation of the PTMs and normalization of the PTM abnormalities could be useful as methods to control various cellular mechanisms and as a therapeutic strategy, respectively. To modulate the PTMs, we have focused on lysine-modifying enzymes and have pursued drug discovery researches on ubiquitination inducers, lysine deacetylase (KDAC) inhibitors, and lysine demethylase (KDM) inhibitors. For the identification of the modulators, we have used not only conventional drug design, such as structure-based drug design (SBDD) and ligand-based drug design (LBDD), but also "strategic chemistry approaches," such as drug design based on enzyme catalytic mechanism. As a result, we have identified several modulators which have pharmacological effects in animal models or in cellular studies. In this review, focusing on the drug design based on enzyme catalytic mechanism, our drug discovery researches have been discussed.

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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

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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>

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Identification of ortho-hydroxy anilide as a novel scaffold for lysine demethylase 5 inhibitors

Cited by 6 publications

References 32 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

Drug Discovery Researches on Modulators of Lysine-Modifying Enzymes Based on Strategic Chemistry Approaches

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

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