Development and evaluation of selective, reversible LSD1 inhibitors derived from fragments

Hitchin, James R.; Blagg, Julian; Burke, Rosemary; Burns, Samantha; Cockerill, Mark; Fairweather, Emma; Hutton, Colin; Jordan, Allan M.; McAndrew, Craig; Mirza, Amin; Mould, Daniel P.; Thomson, Graeme; Waddell, Ian D.; Ogilvie, Donald

doi:10.1039/c3md00226h

Cited by 62 publications

(64 citation statements)

References 27 publications

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“…However, these compounds were toxic to cells at high concentration, which limits their application in cellular studies., On the other hand, they confirmed GSK354 as a reversible inhibitor of LSD1 and reported that this compound displayed high potency and selectivity to LSD1 without cytotoxicity at low concentration (Hitchin et al, 2013) (Table 1). By means of structure-based virtual screening (VS) of ∼2 million compounds, a potent and selective LSD1 inhibitor, compound 12 (a Nʹ -(1-phenylethylidene) benzohydrazide analogue), was discovered, which specifically inhibits H3K9me2 demethylation of LSD1 (Sorna et al, 2013) (Table 1).…”

Section: Lsd1/2: Mono-and Di-methyl Lysine Histone Demethylasesmentioning

confidence: 89%

Epigenetic targets and drug discovery Part 2: Histone demethylation and DNA methylation

Liu

Lau

et al. 2015

Pharmacology & Therapeutics

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Section: Lsd1/2: Mono-and Di-methyl Lysine Histone Demethylasesmentioning

confidence: 89%

Epigenetic targets and drug discovery Part 2: Histone demethylation and DNA methylation

Liu

Lau

et al. 2015

Pharmacology & Therapeutics

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“…This has led to the production of bizine 32, an LSD1 selective inhibitor analogue of 31, capable of modulating bulk histone methylation in cancer cells [155]. An important step in producing these new LSD1 inhibitors is to reduce MAO binding while retaining KDM inhibition activity [156]. The 3,5-diamino 1,2,4-triazoles similar to 33 are potent, selective and reversible inhibitors of LSD1 (IC 50 = 1-2 μM) with minimal activity toward MAO-A and MAO-B (IC 50 > 100 μM) [157].…”

Section: Lysine Demethylase Inhibitorsmentioning

confidence: 99%

Inhibitors of Enzymes Catalyzing Modifications to Histone Lysine Residues: Structure, Function and Activity

et al. 2016

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Gene expression is partly controlled by epigenetic mechanisms including histone-modifying enzymes. Some diseases are caused by changes in gene expression that can be mitigated by inhibiting histone-modifying enzymes. This review covers the enzyme inhibitors targeting histone lysine modifications. We summarize the enzymatic mechanisms of histone lysine acetylation, deacetylation, methylation and demethylation and discuss the biochemical roles of these modifications in gene expression and in disease. We discuss inhibitors of lysine acetylation, deacetylation, methylation and demethylation defining their structure-activity relationships and their potential mechanisms. We show that there are potentially indiscriminant off-target effects on gene expression even with the use of selective epigenetic enzyme inhibitors.

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“…[71] For example, the introduction of bulkier groups to the benzene ring in the tranylcypromine compounds is an effective route to increase LSD1 inhibition and selectivity. [73] Recently, Tortorici et al reported noncovalent binding peptides based on sequence similarity to the N-terminal region of the SNAIL1 transcriptional regulator, exhibiting low-micromolar inhibitory activity. These compounds bind in the H3 tail binding cleft by forming a covalent adduct with the FAD cofactor.…”

Section: Lsd1 Inhibitorsmentioning

confidence: 99%

“…[73] Recently, Tortorici et al reported noncovalent binding peptides based on sequence similarity to the N-terminal region of the SNAIL1 transcriptional regulator, exhibiting low-micromolar inhibitory activity. [73] Computational modeling of LSD1 catalytic mechanism Wang et al used the molecular mimicry of H3-peptide bound LSD1 crystal structure and synthesized nine novel inhibitors containing a guanidinium group that mimics the interactions displayed by the arginine residue of the H3 peptide.…”

Section: Lsd1 Inhibitorsmentioning

confidence: 99%

Epigenetic Molecular Recognition: A Biomolecular Modeling Perspective

Vellore

Baron

2014

ChemMedChem

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The abnormal regulation of epigenetic protein families is associated with the onset and progression of various human diseases. However, epigenetic processes remain relatively obscure at the molecular level, thus preventing the rational design of chemical therapeutics. An array of robust computational and modeling approaches can complement experiments to shed light on the complex mechanisms of epigenetic molecular recognition and can guide medicinal chemists in designing selective and potent drug molecules. Herein we present a review of studies focused on epigenetic molecular recognition from a biomolecular modeling viewpoint. Although the known epigenetic targets are numerous, this review focuses on the more limited protein families on which computational modeling has been successfully applied. Therefore, we review three main topics: 1) histone deacetylases, 2) histone demethylases, and 3) histone tail dynamics. A brief review of the biological background and biomedical relevance is presented for each topic, followed by a detailed discussion of the computational studies and their relevance.

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Development and evaluation of selective, reversible LSD1 inhibitors derived from fragments

Cited by 62 publications

References 27 publications

Epigenetic targets and drug discovery Part 2: Histone demethylation and DNA methylation

Epigenetic targets and drug discovery Part 2: Histone demethylation and DNA methylation

Inhibitors of Enzymes Catalyzing Modifications to Histone Lysine Residues: Structure, Function and Activity

Epigenetic Molecular Recognition: A Biomolecular Modeling Perspective

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