Abstract：
:Protein arginine methylation is a posttranslational modification critical for a variety of biological processes. Misregulation of protein arginine methyltransferases (PRMTs) has been linked to many pathological conditions. Most current PRMT inhibitors display limited specificity and selectivity, indiscriminately targeting many methyltransferase enzymes that use S-adenosyl-l-methionine as a cofactor. Here we report diamidine compounds for specific inhibition of PRMT1, the primary type I enzyme. Docking, molecular dynamics, and MM/PBSA analysis together with biochemical assays were conducted to understand the binding modes of these inhibitors and the molecular basis of selective inhibition for PRMT1. Our data suggest that 2,5-bis(4-amidinophenyl)furan (1, furamidine, DB75), one leading inhibitor, targets the enzyme active site and is primarily competitive with the substrate and noncompetitive toward the cofactor. Furthermore, cellular studies revealed that 1 is cell membrane permeable and effectively inhibits intracellular PRMT1 activity and blocks cell proliferation in leukemia cell lines with different genetic lesions.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Yan L,Yan C,Qian K,Su H,Kofsky-Wofford SA,Lee WC,Zhao X,Ho MC,Ivanov I,Zheng YGdoi
10.1021/jm401884zsubject
Has Abstractpub_date
2014-03-27 00:00:00pages
2611-22issue
6eissn
0022-2623issn
1520-4804journal_volume
57pub_type
杂志文章abstract：:Quantitative structure-activity relationships (QSAR) have been established for the inhibition of dihydrofolate reductase and thymidylate synthetase by 2,4-diaminoquinazoline-glutamic acid analogues. For dihydrofolate reductase from both human acute lymphocytic leukemia cells and murine L1210R cells, QSAR's obtained wi...
journal_title：Journal of medicinal chemistry
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abstract：:Current drugs for the treatment of seizure disorders, although effective in many patients, still suffer from a number of failures and are not effective in some forms of resistant epilepsies. Historically, many of these drugs have multiple mechanisms of action including calcium and sodium channel blockade as well as GA...
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journal_title：Journal of medicinal chemistry
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abstract：:4,6,6a,7,8,12b-Hexahydroindolo[4,3-ab]phenanthridines ("benzergolines") was the first structural class of potent and selective dopamine D1 agonists lacking a catechol group. In order to determine the enantioselectivity of the 7-methyl derivative in the adenylate cyclase assay, its 5,5a-dihydro precursor was resolved a...
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doi：10.1021/jm00062a002
更新日期：1993-05-14 00:00:00
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更新日期：2009-12-10 00:00:00
abstract：:Tyrosine kinases often play pivotal roles in the pathogenesis of cancer and are good candidates for therapeutic intervention and targeted molecular imaging. The precursor synthesis, radiosynthesis, and biological characterization of a fluorine-18 analog of dasatinib, a multitargeted kinase inhibitor, are reported. Com...
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更新日期：2007-11-15 00:00:00
abstract：:A number of 2-oxoquinoline-1-alkanoic acids that contain the N-acylglycine fragment found in several known inhibitors of aldose reductase were synthesized and tested in the rat lens assay. All of the target compounds were prepared by alkylation of the appropriate 2-oxoquinoline intermediates with a halo ester, followe...
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pub_type： 杂志文章
doi：10.1021/jm00160a038
更新日期：1986-10-01 00:00:00
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journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm991007y
更新日期：1999-06-17 00:00:00
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doi：10.1021/jm0308038
更新日期：2003-07-31 00:00:00
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pub_type： 杂志文章
doi：10.1021/acs.jmedchem.9b00260
更新日期：2019-07-25 00:00:00
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journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.7b00343
更新日期：2017-06-22 00:00:00
abstract：:Recent efforts to identify treatments for chronic diabetic complications have resulted in the discovery of a novel series of highly potent and selective 3-[(benzothiazol-2-yl)methyl]indole-N-alkanoic acid aldose reductase inhibitors. The lead candidate, 3-[(4,5,7-trifluorobenzothiazol-2-yl)methyl]indole-N-acetic acid ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0492094
更新日期：2005-05-05 00:00:00
abstract：:G protein-coupled receptors (GPCRs) belong to a large superfamily of membrane receptors mediating a variety of physiological functions. As such they are attractive targets for drug therapy. However, it remains a challenge to develop subtype selective GPCR ligands due to the high conservation of orthosteric binding sit...
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更新日期：2017-05-25 00:00:00
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journal_title：Journal of medicinal chemistry
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更新日期：1994-02-18 00:00:00
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journal_title：Journal of medicinal chemistry
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doi：10.1021/jm800321h
更新日期：2008-09-11 00:00:00
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doi：10.1021/jm00187a022
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journal_title：Journal of medicinal chemistry
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更新日期：2008-07-10 00:00:00
abstract：:G-protein-coupled receptor 52 (GPR52) is an orphan Gs-coupled G-protein-coupled receptor. GPR52 inhibits dopamine D2 receptor signaling and activates dopamine D1/N-methyl-d-aspartate receptors via intracellular cAMP accumulation, and therefore, GPR52 agonists may have potential as a novel class of antipsychotics. A se...
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更新日期：2014-06-26 00:00:00
abstract：:The human immunodeficiency virus type 1 (HIV-1) is a major health problem worldwide. In this study, 17 analogues of L-chicoric acid, a potent inhibitor of HIV integrase, were studied. Of these analogues, five submicromolar inhibitors of integrase were discovered and 13 compounds with activity against integrase at less...
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更新日期：2002-08-15 00:00:00
abstract：:Thrombin is a serine protease responsible for blood coagulation. Since thrombin inhibitors appear to be effective in the treatment and prevention of thrombotic and embolic disorders, considerable attention has been focused on the structure and interactions of this enzyme. In this work, to evaluate the relative free en...
journal_title：Journal of medicinal chemistry
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更新日期：2002-11-07 00:00:00
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journal_title：Journal of medicinal chemistry
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更新日期：1998-09-24 00:00:00
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更新日期：1998-06-18 00:00:00
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更新日期：2006-04-06 00:00:00
abstract：:Several new 1-substituted 3,5-dimethylpyrazoles were prepared for testing as hypoglycemic agents. A number of these containing para-substituted 1-carbonylphenylurea and para-substituted 1-carbamoylbenzenesulfonylurea derivatives were found to possess potent hypoglycemic activity. ...
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pub_type： 杂志文章
doi：10.1021/jm00365a023
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abstract：:On the basis of results previously obtained from structural and theoretical studies on beta-adrenergic drugs, a series of aliphatic oxime ether derivatives (AOEDs) was synthesized. As expected, pharmacological in vitro tests showed that compounds examined exhibit a marked and competitive antagonism at beta-adrenocepto...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00380a001
更新日期：1985-02-01 00:00:00
