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Adding a lysine mimic in the design of potent inhibitors of histone lysine methyltransferases.

Chang Y, Ganesh T, Horton JR, Spannhoff A, Liu J, Sun A, Zhang X, Bedford MT, Shinkai Y, Snyder JP, Cheng X
J Mol Biol 400 1-7 (2010)
Related entries: 3mo0, 3mo2

Cited: 64 times
EuropePMC logo PMID: 20434463

Abstract

Dynamic histone lysine methylation involves the activities of modifying enzymes (writers), enzymes removing modifications (erasers), and readers of the histone code. One common feature of these activities is the recognition of lysines in methylated and unmethylated states, whether they are substrates, reaction products, or binding partners. We applied the concept of adding a lysine mimic to an established inhibitor (BIX-01294) of histone H3 lysine 9 methyltransferases G9a and G9a-like protein by including a 5-aminopentyloxy moiety, which is inserted into the target lysine-binding channel and becomes methylated by G9a-like protein, albeit slowly. The compound enhances its potency in vitro and reduces cell toxicity in vivo. We suggest that adding a lysine or methyl-lysine mimic should be considered in the design of small-molecule inhibitors for other methyl-lysine writers, erasers, and readers.

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  4. Deep Neural Network Classifier for Virtual Screening Inhibitors of (S)-Adenosyl-L-Methionine (SAM)-Dependent Methyltransferase Family. Li F, Wan X, Xing J, Tan X, Li X, Wang Y, Zhao J, Wu X, Liu X, Li Z, Luo X, Lu W, Zheng M. Front Chem 7 324 (2019)


Reviews citing this publication (24)

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Articles citing this publication (34)

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  3. Discovery of an in vivo chemical probe of the lysine methyltransferases G9a and GLP. Liu F, Barsyte-Lovejoy D, Li F, Xiong Y, Korboukh V, Huang XP, Allali-Hassani A, Janzen WP, Roth BL, Frye SV, Arrowsmith CH, Brown PJ, Vedadi M, Jin J. J Med Chem 56 8931-8942 (2013)
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  10. 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. J Med Chem 56 2110-2124 (2013)
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  13. A fluorescence-based supramolecular tandem assay for monitoring lysine methyltransferase activity in homogeneous solution. Florea M, Kudithipudi S, Rei A, González-Álvarez MJ, Jeltsch A, Nau WM. Chemistry 18 3521-3528 (2012)
  14. Regulation of USP37 Expression by REST-Associated G9a-Dependent Histone Methylation. Dobson THW, Hatcher RJ, Swaminathan J, Das CM, Shaik S, Tao RH, Milite C, Castellano S, Taylor PH, Sbardella G, Gopalakrishnan V. Mol Cancer Res 15 1073-1084 (2017)
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  16. Analogues of the Natural Product Sinefungin as Inhibitors of EHMT1 and EHMT2. Devkota K, Lohse B, Liu Q, Wang MW, Stærk D, Berthelsen J, Clausen RP. ACS Med Chem Lett 5 293-297 (2014)
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  18. Polymyxins and quinazolines are LSD1/KDM1A inhibitors with unusual structural features. Speranzini V, Rotili D, Ciossani G, Pilotto S, Marrocco B, Forgione M, Lucidi A, Forneris F, Mehdipour P, Velankar S, Mai A, Mattevi A. Sci Adv 2 e1601017 (2016)
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  21. Exploration of cyanine compounds as selective inhibitors of protein arginine methyltransferases: synthesis and biological evaluation. Hu H, Owens EA, Su H, Yan L, Levitz A, Zhao X, Henary M, Zheng YG. J Med Chem 58 1228-1243 (2015)
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  29. In silico probing and biological evaluation of SETDB1/ESET-targeted novel compounds that reduce tri-methylated histone H3K9 (H3K9me3) level. Park I, Hwang YJ, Kim T, Viswanath ANI, Londhe AM, Jung SY, Sim KM, Min SJ, Lee JE, Seong J, Kim YK, No KT, Ryu H, Pae AN. J Comput Aided Mol Des 31 877-889 (2017)
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  31. Histone mimics: digging down under. Lin Y, Zhou BP. Front Biol (Beijing) 8 228-233 (2013)
  32. Discovery of the First-in-Class G9a/GLP Covalent Inhibitors. Park KS, Xiong Y, Yim H, Velez J, Babault N, Kumar P, Liu J, Jin J. J Med Chem 65 10506-10522 (2022)
  33. Mimicking H3 Substrate Arginine in the Design of G9a Lysine Methyltransferase Inhibitors for Cancer Therapy: A Computational Study for Structure-Based Drug Design. Chandar Charles MR, Li MC, Hsieh HP, Coumar MS. ACS Omega 6 6100-6111 (2021)
  34. Structure-Based Virtual Screening and in vitro and in vivo Analyses Revealed Potent Methyltransferase G9a Inhibitors as Prospective Anti-Alzheimer's Agents. Bellver-Sanchis A, Singh Choudhary B, Companys-Alemany J, Sukanya, Ávila-López PA, Martínez Rodríguez AL, Brea Floriani JM, Malik R, Pallàs M, Pérez B, Griñán-Ferré C. ChemMedChem 17 e202200002 (2022)


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