DNA-methyltransferase activities in<i>Streptomyces antibioticus</i>

Barbés, Covadonga; Hardisson, Carlos; Novella, Isabel S.; Yebra, Marı́a J.; Sánchez, Jesús

doi:10.1111/j.1574-6968.1988.tb02798.x

Cited by 9 publications

(3 citation statements)

References 19 publications

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“…Sinefungin A, isolated from Streptomyces, is a natural nucleoside analog of SAM and a non-selective inhibitor of KMTs. 9 Chaetocin, a fungal metabolite, was discovered next, as an inhibitor of Suv39H1. 10 It demonstrated some dose-dependent selectivity, when not additionally inhibiting EZH1-2 or SET7/ 9, at concentrations below 90 μM.…”

Section: Introductionmentioning

confidence: 99%

Histone demethylating agents as potential S-adenosyl-l-methionine-competitors

et al. 2016

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Histone H3 methylation on K9 and/or K27 depends on histone lysine methyltransferases (KMTs). EZH2, one of the components of the PRC2 complex, catalyzes the trimethylation of histone H3K27, which is associated with transcriptional repression and tumor development. H3K9me3 mediated gene silencing may result from other KDMs such as G9a/GLP, SUV39H1-2, SETDB1, CCLD8 and RIZ1. Their disturbance leads to defective cell mitosis. It is therefore desirable to find small molecules that are able to decrease H3K9 and K27 tagging to reinitiate gene transcription. Most KDM inhibitors are still based on SAM co-factor competition/modulation. Herein, functional screening of a diversity library proved to be a useful tool for finding new specific KDM inhibitors; the use of SAM-based pharmacophoric models facilitated the understanding of their possible mechanism of action

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Section: Introductionmentioning

confidence: 99%

Histone demethylating agents as potential S-adenosyl-l-methionine-competitors

et al. 2016

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“…Most efforts were dedicated to small molecule inhibitors discovery, such as the earliest-reported SAM analogues. [22][23][24][25][26][27] A common drawback of this class of inhibitors is the lack of selectivity against PRMT1 over other enzymes utilizing nonspecific SAM as the methyl donor. Also, naphthyl-sulfo (NS) molecules like AMI-1 11,28,29 are reported to inhibit the transcriptional activation of hormone receptors through targeting the PRMT1 arginine pocket, implicating the treatment of leukemia.…”

Section: Introductionmentioning

confidence: 99%

Virtual screening and biological evaluation of novel small molecular inhibitors against protein arginine methyltransferase 1 (PRMT1)

et al. 2014

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Protein arginine methylation is a common post-translational modification which is crucial for a variety of biological processes. Dysregulation of protein arginine methyltransferases (PRMTs) activity has been implicated in cancer and other serious diseases. Thus, small molecule inhibitors against PRMT have great potential for therapeutic development. Herein, through the combination of virtual screening and bioassays, six small molecular compounds were identified as PRMT1 inhibitors. Amongst them, the binding affinity of compounds DCLX069 and DCLX078 with PRMT1 was further validated by T1ρ and saturation transfer difference (STD) NMR experiments. Most important of all, both compounds effectively blocked cell proliferation in breast cancer, liver cancer and acute myeloid leukemia cell lines. The binding mode analysis from molecular docking simulations theoretically indicated that both inhibitors occupied the SAM binding pocket to exert the inhibitory effect. Taken together, our compounds enriched the structural scaffolds as PRMT1 inhibitors and afforded clues for further optimization.

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“…[18] Nevertheless, the pan-antimethylation activity of simple SAM analogs limited their applications as PRMT1 inhibitors. SAM analogs, such as sinefungin and SAH, were initially used as chemical tools to investigate PRMT1 function.…”

Section: Introductionmentioning

confidence: 99%

Discovery of alkyl bis(oxy)dibenzimidamide derivatives as novel protein arginine methyltransferase 1 (PRMT1) inhibitors

Zhang

Jiang

et al. 2017

Chem Biol Drug Des

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Protein arginine methylation, a post-translational modification critical for a variety of biological processes, is catalyzed by protein arginine N-methyltransferases (PRMTs). In particular, PRMT1 is responsible for over 85% of the arginine methylation in mammalian cells. Dysregulation of PRMT1 is involved in diverse pathological diseases including cancers. However, most current PRMT1 inhibitors are lack of specificity, efficacy, and bioavailability. Herein, a series of alkyl bis(oxy)dibenzimidamide derivatives were identified as selective PRMT1 inhibitors. Among them, the most potent compound corresponds to hexamidine (IC = 5.9 ± 1.7 μm), which is an antimicrobial agent. The binding between hexamidine and PRMT1 was further validated by thermal shift assays and nuclear magnetic resonance (NMR) experiments. Molecular docking and NMR assays indicated that hexamidine occupied the substrate binding pocket. Furthermore, hexamidine effectively blocked cell proliferation in cancer cell lines related to PRMT1 overexpression. Taken together, this study has provided a druggable scaffold targeting PRMT1 as well as a new way to repurpose old drugs which is a complementary tool for the discovery of new lead compounds.

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DNA-methyltransferase activities inStreptomyces antibioticus

Cited by 9 publications

References 19 publications

Histone demethylating agents as potential S-adenosyl-l-methionine-competitors

Histone demethylating agents as potential S-adenosyl-l-methionine-competitors

Virtual screening and biological evaluation of novel small molecular inhibitors against protein arginine methyltransferase 1 (PRMT1)

Discovery of alkyl bis(oxy)dibenzimidamide derivatives as novel protein arginine methyltransferase 1 (PRMT1) inhibitors

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