Discovery of a Novel Chemotype of Histone Lysine Methyltransferase EHMT1/2 (GLP/G9a) Inhibitors: Rational Design, Synthesis, Biological Evaluation, and Co-crystal Structure

Milite, Ciro; Feoli, Alessandra; Horton, J.R.; Rescigno, Donatella; Cipriano, Alessandra; Pisapia, Vincenzo; Viviano, Monica; Pepe, Giacomo; Amendola, Giorgio; Novellino, Ettore; Cosconati, Sandro; Cheng, Xiaodong; Castellano, Sabrina; Sbardella, Gianluca

doi:10.1021/acs.jmedchem.8b02008

Cited by 36 publications

(46 citation statements)

References 125 publications

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“…All compounds were dissolved in DMSO (100%) to obtain 50 mM solutions and diluted in HBS-P (10 mM HEPES pH 7.4, 0.15 M NaCl, 0.005% surfactant P20), always maintaining a final 0.2% DMSO concentration. Binding experiments were performed as previously described [62].…”

Section: Surface Plasmon Resonancementioning

confidence: 99%

Two novel SIRT1 activators, SCIC2 and SCIC2.1, enhance SIRT1-mediated effects in stress response and senescence

et al. 2020

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Nebbioso (2020) Two novel SIRT1 activators, SCIC2 and SCIC2.1, enhance SIRT1-mediated effects in stress response and senescence, Epigenetics, 15:6-7, 664-683, ABSTRACT SIRT1, a NAD + -dependent deacetylase, is the most well-studied member of class III histone deacetylases. Due to its wide range of activities and substrate targets, this enzyme has emerged as a major regulator of different physiological processes. However, SIRT1-mediated alterations are also implicated in the pathogenesis of several conditions, including metabolic and neurodegenerative disorders, and cancer. Current evidence highlights the potential role of SIRT1 as an attractive therapeutic target for disease prevention and treatment strategies, thus propelling the development of new pharmacological agents. By high-throughput screening of a large library of compounds, we identified SCIC2 as an effective SIRT1 activator. This small molecule showed enzymatic activity of 135.8% at 10 μM, an AC 50 value of 50 ± 1.8 µM, and bound SIRT1 with a K D of 26.4 ± 0.6 μM. In order to potentiate its SIRT1-activating ability, SCIC2 was subjected to modelling studies, leading to the identification of a more potent derivative, SCIC2.1. SCIC2.1 displayed higher SIRT1 activity (175%; AC 50 = 36.83 ± 2.23 µM), stronger binding to SIRT1, and greater cell permeability than SCIC2. At cellular level, both molecules did not alter the cell cycle progression of cancer cells and normal cells, and were able to strengthen SIRT1-mediated effects in stress response. Finally, SCIC2 and SCIC2.1 attenuated induction of senescence by reducing senescenceassociated β-galactosidase activity. Our findings warrant further investigation of these two novel SIRT1 activators in in vivo and human studies. ARTICLE HISTORY

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Section: Surface Plasmon Resonancementioning

confidence: 99%

Two novel SIRT1 activators, SCIC2 and SCIC2.1, enhance SIRT1-mediated effects in stress response and senescence

et al. 2020

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“…Given the evidence demonstrating the implication of the G9a/GLP complex in different human diseases, it has emerged as a promising pharmacological target, and several small-molecules have been designed to inhibit these enzymes [24]. Optimization of these molecules lead to UNC0642, a compound with IC 50 < 2.5 nM and optimized pharmacokinetics (PK) [24, 25]. This inhibitor of G9a/GLP was the first in vivo chemical probe with high potency in reducing H3K9me2 levels, and low cell toxicity (EC 50 > 3,000 nM).…”

Section: Introductionmentioning

confidence: 99%

Pharmacological inhibition of G9a/GLP restores cognition and reduces oxidative stress, neuroinflammation and β-Amyloid plaques in an early-onset Alzheimer’s disease mouse model

Griñán-Ferré

Marsal-García

Bellver-Sanchis

et al. 2019

Aging

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The implication of epigenetic mechanisms in Alzheimer’s disease (AD) has been demonstrated in several studies. UNC0642, a specific and potent inhibitor of methyltransferase activity G9a/GLP (G9a-like) complex, was evaluated in the 5XFAD mouse model. UNC0642 treatment rescued 5XFAD cognition impairment, reduced DNA-methylation (5-mC), increased hydroxymethylation (5-hmC), and decreased the di-methylation of lysine 9 of histone H3 (H3K9me2) levels in the hippocampus. Increases in the Nuclear Factor erythroid-2-Related Factor 2 (NRF2), Heme oxygenase decycling 1 (Hmox1) gene expression, and diminution in Reactive Oxygen Species (ROS) were also reported. Moreover, neuroinflammatory markers, such as Interleukin 6 (Il-6), Tumor necrosis factor-alpha (Tnf-α) gene expression, and Glial fibrillary acidic protein (GFAP) immunofluorescence were reduced by UNC0642 treatment. An increase in Nerve growth factor (Ngf), Nerve growth factor inducible (Vgf) gene expression, Brain-derived neurotrophic factor (BDNF), and Synaptophysin (SYN) were found after UNC0642 treatment. Importantly, a reduction in β-amyloid plaques was also observed. In conclusion, our work demonstrates that the inhibition of the G9a/GLP complex by UNC0642 delivered significant neuroprotective effects in 5XFAD mice, point out G9a/GLP as a new target for AD.

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“…Often G9a and GLP activities are described as inhibitory targets for cancer treatment (Casciello et al, 2015;Charles et al, 2019;Milite et al, 2019); for example, Huang and colleagues reported G9a and GLP to be overexpressed in a variety of cancers, denoting them as candidate oncogenes (Huang et al, 2010). Supporting this, a higher G9a expression has been correlated with poor prognosis in terms of clinicopathological features of gastric cancer and poor patient outcomes (Zhang et al, 2019).…”

Section: Hypoxic Methylation and Pathological Relevancementioning

confidence: 99%

“…The development of pharmacological inhibitors of G9a and/or GLP has resulted in a capability to selectively inhibit these KMTs ( Charles et al, 2019 ; Milite et al, 2019 ). However, caution in the use of G9a inhibition as a therapeutic strategy in cancer has recently been advocated ( Seton-Rogers, 2019 ).…”

Section: Hypoxic Methylation and Pathological Relevancementioning

confidence: 99%

Hypoxia-Inducible Lysine Methyltransferases: G9a and GLP Hypoxic Regulation, Non-histone Substrate Modification, and Pathological Relevance

et al. 2020

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Oxygen sensing is inherent among most animal lifeforms and is critical for organism survival. Oxygen sensing mechanisms collectively trigger cellular and physiological responses that enable adaption to a reduction in ideal oxygen levels. The major mechanism by which oxygen-responsive changes in the transcriptome occur are mediated through the hypoxia-inducible factor (HIF) pathway. Upon reduced oxygen conditions, HIF activates hypoxia-responsive gene expression programs. However, under normal oxygen conditions, the activity of HIF is regularly suppressed by cellular oxygen sensors; prolyl-4 and asparaginyl hydroxylases. Recently, these oxygen sensors have also been found to suppress the function of two lysine methyltransferases, G9a and G9a-like protein (GLP). In this manner, the methyltransferase activity of G9a and GLP are hypoxia-inducible and thus present a new avenue of low-oxygen signaling. Furthermore, G9a and GLP elicit lysine methylation on a wide variety of non-histone proteins, many of which are known to be regulated by hypoxia. In this article we aim to review the effects of oxygen on G9a and GLP function, non-histone methylation events inflicted by these methyltransferases, and the clinical relevance of these enzymes in cancer.

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Discovery of a Novel Chemotype of Histone Lysine Methyltransferase EHMT1/2 (GLP/G9a) Inhibitors: Rational Design, Synthesis, Biological Evaluation, and Co-crystal Structure

Cited by 36 publications

References 125 publications

Two novel SIRT1 activators, SCIC2 and SCIC2.1, enhance SIRT1-mediated effects in stress response and senescence

Two novel SIRT1 activators, SCIC2 and SCIC2.1, enhance SIRT1-mediated effects in stress response and senescence

Pharmacological inhibition of G9a/GLP restores cognition and reduces oxidative stress, neuroinflammation and β-Amyloid plaques in an early-onset Alzheimer’s disease mouse model

Hypoxia-Inducible Lysine Methyltransferases: G9a and GLP Hypoxic Regulation, Non-histone Substrate Modification, and Pathological Relevance

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