Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:6.2.1.1 (ACS)
 78,556 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Trimethylation of histone H3 Lys4 (H3K4) is associated with transcriptional activation. One of the chief effectors of H3K4 methylation is mixed-lineage leukemia 1 (MLL1), a gene that is disrupted by chromosomal translocation in acute leukemia and a master regulator of Hox and other genes. In a recent paper, core components of the human MLL histone methyltransferase (MT) complex were found to form a structural platform, with one component (WDR5) mediating association between the specific histone H3K4 substrate and the MT. This novel regulatory mechanism, which is conserved from yeast to human, is required for both methylation and downstream target gene transcription.
ACS Chem Biol 2006 Sep 19
PMID:MLL core components give the green light to histone methylation. 1716 35

Post-translational modifications of histones alter chromatin structure and play key roles in gene expression and specification of cell states. Small molecules that target chromatin-modifying enzymes selectively are useful as probes and have promise as therapeutics, although very few are currently available. G9a (also named euchromatin histone methyltransferase 2 (EHMT2)) catalyzes methylation of lysine 9 on histone H3 (H3K9), a modification linked to aberrant silencing of tumor-suppressor genes, among others. Here, we report the discovery of a novel histone methyltransferase inhibitor, BRD4770. This compound reduced cellular levels of di- and trimethylated H3K9 without inducing apoptosis, induced senescence, and inhibited both anchorage-dependent and -independent proliferation in the pancreatic cancer cell line PANC-1. ATM-pathway activation, caused by either genetic or small-molecule inhibition of G9a, may mediate BRD4770-induced cell senescence. BRD4770 may be a useful tool to study G9a and its role in senescence and cancer cell biology.
ACS Chem Biol 2012 Jul 20
PMID:A small-molecule probe of the histone methyltransferase G9a induces cellular senescence in pancreatic adenocarcinoma. 2253 50

Neurogenesis consists of a plethora of complex cellular processes including neural stem cell (NSC) proliferation, migration, maturation or differentiation to neurons, and finally integration into the pre-existing neural circuits in the brain, which are temporally regulated and coordinated sequentially. Mammalian neurogenesis begins during embryonic development and continues in postnatal brain (adult neurogenesis). It is now evident that adult neurogenesis is driven by extracellular and intracellular signaling pathways, where epigenetic modifications like reversible histone acetylation, methylation, as well as DNA methylation play a vital role. Epigenetic regulation of gene expression during neural development is governed mainly by histone acetyltransferases (HATs), histone methyltransferase (HMTs), DNA methyltransferases (DNMTs), and also the enzymes for reversal, like histone deacetylases (HDACs), and many of these have also been shown to be involved in the regulation of adult neurogenesis. The contribution of these epigenetic marks to neurogenesis is increasingly being recognized, through knockout studies and small molecule modulator based studies. These small molecules are directly involved in regeneration and repair of neurons, and not only have applications from a therapeutic point of view, but also provide a tool to study the process of neurogenesis itself. In the present Review, we will focus on small molecules that act predominantly on epigenetic enzymes to enhance neurogenesis and neuroprotection and discuss the mechanism and recent advancements in their synthesis, targeting, and biology.
ACS Chem Neurosci 2014 Dec 17
PMID:Modulation of neurogenesis by targeting epigenetic enzymes using small molecules: an overview. 2525 Jun 44

The histone methyltransferase DOT1L, solely responsible for histone H3 lysine 79 (H3K79) methylation, is associated with gene activation. Human leukemias carrying MLL gene rearrangements aberrantly recruit DOT1L to leukemogenic genes leading to increased H3K79 methylation and their transcriptional activation. Recent studies suggest that Wnt-targeted genes also depend on H3K79 methylation. Employing a chemical biology approach, the requirement for H3K79 methylation was investigated in Wnt pathway-inducible HEK293 cells and human colon adenocarcinoma-derived cell lines by inhibiting DOT1L with EPZ004777, a selective and potent S-adenosylmethionine competitive inhibitor. Our findings indicate that H3K79 methylation is not essential for the canonical Wnt signaling pathway, in particular for maintenance or activation of Wnt pathway target gene expression. Furthermore, H3K79 methylation is not elevated in human colon carcinoma samples in comparison with normal colon tissue. Therefore, our findings indicate that inhibition of DOT1L histone methyltransferase activity is likely not a viable therapeutic strategy in colon cancer.
ACS Chem Biol 2015 Jan 16
PMID:Regulation of Wnt signaling target gene expression by the histone methyltransferase DOT1L. 2536 Nov 63

SMYD3 has been implicated in a range of cancers; however, until now no potent selective small molecule inhibitors have been available for target validation studies. A novel oxindole series of SMYD3 inhibitors was identified through screening of the Epizyme proprietary histone methyltransferase-biased library. Potency optimization afforded two tool compounds, sulfonamide EPZ031686 and sulfamide EPZ030456, with cellular potency at a level sufficient to probe the in vitro biology of SMYD3 inhibition. EPZ031686 shows good bioavailability following oral dosing in mice making it a suitable tool for potential in vivo target validation studies.
ACS Med Chem Lett 2016 Feb 11
PMID:Novel Oxindole Sulfonamides and Sulfamides: EPZ031686, the First Orally Bioavailable Small Molecule SMYD3 Inhibitor. 2698 87

Mixed lineage leukemia (MLL) gene rearrangement induces leukemic transformation by ectopic recruitment of disruptor of telomeric silencing 1-like protein (DOT1L), a lysine histone methyltransferase, leading to local hypermethylation of H3K79 and misexpression of genes (including HoxA), which drive the leukemic phenotype. A weak fragment-based screening hit identified by SPR was cocrystallized with DOT1L and optimized using structure-based ligand optimization to yield compound 8 (IC50 = 14 nM). This series of inhibitors is structurally not related to cofactor SAM and is not interacting within the SAM binding pocket but induces a pocket adjacent to the SAM binding site.
ACS Med Chem Lett 2016 Aug 11
PMID:Optimization of a Fragment-Based Screening Hit toward Potent DOT1L Inhibitors Interacting in an Induced Binding Pocket. 2756 94

Oncogenic MLL fusion proteins aberrantly recruit Dot1L, a histone methyltransferase, to ectopic loci, leading to local hypermethylation of H3K79 and misexpression of HoxA genes driving MLL-rearranged leukemias. Inhibition of the methyltransferase activity of Dot1L in this setting is predicted to reverse aberrant H3K79 methylation, leading to repression of leukemogenic genes and tumor growth inhibition. In the context of our Dot1L drug discovery program, high-throughput screening led to the identification of 2, a weak Dot1L inhibitor with an unprecedented, induced pocket binding mode. A medicinal chemistry campaign, strongly guided by structure-based consideration and ligand-based morphing, enabled the discovery of 12 and 13, potent, selective, and structurally completely novel Dot1L inhibitors.
ACS Med Chem Lett 2016 Aug 11
PMID:Discovery of Novel Dot1L Inhibitors through a Structure-Based Fragmentation Approach. 2756 95

Misdirected catalytic activity of histone methyltransferase Dot1L is believed to be causative for a subset of highly aggressive acute leukemias. Targeting the catalytic domain of Dot1L represents a potential therapeutic approach for these leukemias. In the context of a comprehensive Dot1L hit finding strategy, a knowledge-based virtual screen of the Dot1L SAM binding pocket led to the discovery of 2, a non-nucleoside fragment mimicking key interactions of SAM bound to Dot1L. Fragment linking of 2 and 3, an induced back pocket binder identified in earlier studies, followed by careful ligand optimization led to the identification of 7, a highly potent, selective and structurally novel Dot1L inhibitor.
ACS Med Chem Lett 2017 Mar 09
PMID:Discovery of Potent, Selective, and Structurally Novel Dot1L Inhibitors by a Fragment Linking Approach. 2833 27

SMYD3 is a histone methyltransferase that regulates gene transcription, and its overexpression is associated with multiple human cancers. A novel class of tetrahydroacridine compounds which inhibit SMYD3 through a covalent mechanism of action is identified. Optimization of these irreversible inhibitors resulted in the discovery of 4-chloroquinolines, a new class of covalent warheads. Tool compound 29 exhibits high potency by inhibiting SMYD3's enzymatic activity and showing antiproliferative activity against HepG2 in 3D cell culture. Our findings suggest that covalent inhibition of SMYD3 may have an impact on SMYD3 biology by affecting expression levels, and this warrants further exploration.
ACS Med Chem Lett 2019 Jun 13
PMID:Discovery of Irreversible Inhibitors Targeting Histone Methyltransferase, SMYD3. 3141 12

Hepatocellular carcinoma (HCC) is the most common primary liver cancer with high mortality but limited therapeutic options. Epigenetic regulations including DNA methylation and histone modification control gene expressions and play a crucial role during tumorigenesis. G9a, also known as EHMT2 (euchromatic histone-lysine N-methyltransferase 2), is a histone methyltransferase predominantly responsible for dimethylation of histone H3 lysine 9 (H3K9). G9a has been shown to play a key role in promoting tumor progression. Recent studies have identified that G9a is a critical mediator of HCC pathogenesis. UNC0646 is a G9a inhibitor that has shown potent in vitro efficacy. However, due to its water insolubility, the in vivo efficacy of UNC0646 is not satisfactory. In this study, nanodiamonds (NDs) were utilized as a drug delivery platform to improve in vivo delivery of this small-molecule inhibitor. Our results showed that ND-UNC0646 complexes could be rapidly synthesized by physical adsorption, meanwhile possessing favorable drug delivery properties and was able to improve the dispersibility of UNC0646 in water, therefore making it amenable for intravenous administration. The release profile of UNC0646 from ND-UNC0646 was demonstrated to be pH-responsive. Moreover, ND-UNC0646 maintained the biological functionality of UNC0646, with higher efficacy in reducing H3K9 methylation as well as enhanced invasion suppressive effects. Most importantly, increased in vivo efficacy was demonstrated using an orthotopic HCC mouse model, which paves the way of translating this small-molecule inhibitor toward HCC treatment. Our work demonstrates the potential of NDs in the clinical application for HCC treatment.
ACS Appl Mater Interfaces 2019 Dec 11
PMID:Nanodiamond-Mediated Delivery of a G9a Inhibitor for Hepatocellular Carcinoma Therapy. 3171 36


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