Target-based approach to inhibitors of histone arginine methyltransferases - PubMed (original) (raw)
. 2007 May 17;50(10):2319-25.
doi: 10.1021/jm061250e. Epub 2007 Apr 14.
Affiliations
- PMID: 17432842
- DOI: 10.1021/jm061250e
Target-based approach to inhibitors of histone arginine methyltransferases
Astrid Spannhoff et al. J Med Chem. 2007.
Abstract
Lysine and arginine methyltransferases participate in the post-translational modification of histones and regulate key cellular functions. So far only one arginine methyltransferase inhibitor discovered by random screening was available. We present the first target-based approach to protein arginine methyltransferase (PRMT) inhibitors. Homology models of human and Aspergillus nidulans PRMT1 were generated from available X-ray structures of rat PRMTs. The NCI diversity set was filtered by a target-based virtual screening to identify PRMT inhibitors. Employing a fungal PRMT for screening and a human enzyme for validation, we have identified seven inhibitors of PRMTs in vitro. Hit validation was achieved for two new inhibitors by antibody mediated detection of histone hypomethylation as well as Western blotting in cancer cells. Functional activity was proven by an observed block of estrogen receptor activation. Thus, valuable chemical tools and potential drug candidates could be identified.
Similar articles
- Virtual screening and biological characterization of novel histone arginine methyltransferase PRMT1 inhibitors.
Heinke R, Spannhoff A, Meier R, Trojer P, Bauer I, Jung M, Sippl W. Heinke R, et al. ChemMedChem. 2009 Jan;4(1):69-77. doi: 10.1002/cmdc.200800301. ChemMedChem. 2009. PMID: 19085993 - Histone methyltransferases in Aspergillus nidulans: evidence for a novel enzyme with a unique substrate specificity.
Trojer P, Dangl M, Bauer I, Graessle S, Loidl P, Brosch G. Trojer P, et al. Biochemistry. 2004 Aug 24;43(33):10834-43. doi: 10.1021/bi049626i. Biochemistry. 2004. PMID: 15311944 - Small molecule inhibitors of histone arginine methyltransferases: homology modeling, molecular docking, binding mode analysis, and biological evaluations.
Ragno R, Simeoni S, Castellano S, Vicidomini C, Mai A, Caroli A, Tramontano A, Bonaccini C, Trojer P, Bauer I, Brosch G, Sbardella G. Ragno R, et al. J Med Chem. 2007 Mar 22;50(6):1241-53. doi: 10.1021/jm061213n. Epub 2007 Feb 27. J Med Chem. 2007. PMID: 17323938 - Mechanisms and Inhibitors of Histone Arginine Methylation.
Fulton MD, Brown T, Zheng YG. Fulton MD, et al. Chem Rec. 2018 Dec;18(12):1792-1807. doi: 10.1002/tcr.201800082. Epub 2018 Sep 19. Chem Rec. 2018. PMID: 30230223 Free PMC article. Review. - Small Molecule Inhibitors of Protein Arginine Methyltransferases.
Hu H, Qian K, Ho MC, Zheng YG. Hu H, et al. Expert Opin Investig Drugs. 2016;25(3):335-58. doi: 10.1517/13543784.2016.1144747. Epub 2016 Feb 16. Expert Opin Investig Drugs. 2016. PMID: 26789238 Free PMC article. Review.
Cited by
- Methods for Activity Analysis of the Proteins that Regulate Histone Methylation.
Quinn AM, Simeonov A. Quinn AM, et al. Curr Chem Genomics. 2011;5(Suppl 1):95-105. doi: 10.2174/1875397301005010095. Epub 2011 Aug 22. Curr Chem Genomics. 2011. PMID: 21966349 Free PMC article. - Exploiting an allosteric binding site of PRMT3 yields potent and selective inhibitors.
Liu F, Li F, Ma A, Dobrovetsky E, Dong A, Gao C, Korboukh I, Liu J, Smil D, Brown PJ, Frye SV, Arrowsmith CH, Schapira M, Vedadi M, Jin J. Liu F, et al. J Med Chem. 2013 Mar 14;56(5):2110-24. doi: 10.1021/jm3018332. Epub 2013 Feb 27. J Med Chem. 2013. PMID: 23445220 Free PMC article. - Metastasis: recent discoveries and novel treatment strategies.
Eccles SA, Welch DR. Eccles SA, et al. Lancet. 2007 May 19;369(9574):1742-57. doi: 10.1016/S0140-6736(07)60781-8. Lancet. 2007. PMID: 17512859 Free PMC article. Review. - Lung cancer and its association with chronic obstructive pulmonary disease: update on nexus of epigenetics.
Sundar IK, Mullapudi N, Yao H, Spivack SD, Rahman I. Sundar IK, et al. Curr Opin Pulm Med. 2011 Jul;17(4):279-85. doi: 10.1097/MCP.0b013e3283477533. Curr Opin Pulm Med. 2011. PMID: 21537190 Free PMC article. Review. - Inhibitors of Protein Methyltransferases and Demethylases.
Kaniskan HÜ, Martini ML, Jin J. Kaniskan HÜ, et al. Chem Rev. 2018 Feb 14;118(3):989-1068. doi: 10.1021/acs.chemrev.6b00801. Epub 2017 Mar 24. Chem Rev. 2018. PMID: 28338320 Free PMC article. Review.
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Chemical Information