Discovery of Selective Inhibitors for Histone Methyltransferases Histone methyltransferases (HMTs), which catalyze methylation of lysine or arginine residues of histones and non-histone proteins, have been increasingly recognized as major players in regulating gene expression and chromatin state. Growing evidence suggests that HMTs play crucial roles in the development of many human diseases. Thus, HMTs have been increasingly pursued as potential therapeutic targets. However, very few potent, selective and cell-active inhibitors of HMTs have been developed. In this project, we propose to discover high quality inhibitors of HMTs by pursuing three complementary approaches: (1) targeting a novel allosteric binding site; (2) targeting the substrate binding groove; and (3) targeting the cofactor binding site. We have selected PRMT3 (a type I protein arginine methyltransferase), SETD8 (a histone H4 lysine 20 monomethylase), and EZH2 and EZH1 (two closely related histone H3 lysine 27 methyltransferases) as representative HMT targets for these three approaches. We have generated extensive and promising preliminary results for each of the three approaches, suggesting that our proposal is feasible. We expect that successful completion of this project will: (1) produce a set of well-characterized inhibitors as useful tools for the research community to investigate the roles of PRMT3, SETD8 and EZH2/1 in health and disease; and (2) provide strong evidence that potent, selective and cell-active inhibitors of HMTs can be generated by targeting an allosteric binding site, the substrate binding groove and cofactor binding site.
Discovery of Selective Inhibitors for Histone Methyltransferases Growing evidence suggests that histone methyltransferases (HMTs) play critical roles in the development of many human diseases. A `tool-kit' of well-characterized selective inhibitors of HMTs will permit biological and therapeutic hypotheses concerning HMTs to be tested with high confidence in cell-based and/or animal models. In this project, we propose to create multiple selective inhibitors of HMTs for hypothesis testing and target validation.
| Kaniskan, H Ümit; Eram, Mohammad S; Zhao, Kehao et al. (2018) Discovery of Potent and Selective Allosteric Inhibitors of Protein Arginine Methyltransferase 3 (PRMT3). J Med Chem 61:1204-1217 |
| Babault, Nicolas; Allali-Hassani, Abdellah; Li, Fengling et al. (2018) Discovery of Bisubstrate Inhibitors of Nicotinamide N-Methyltransferase (NNMT). J Med Chem 61:1541-1551 |
| Kaniskan, H Ümit; Martini, Michael L; Jin, Jian (2018) Inhibitors of Protein Methyltransferases and Demethylases. Chem Rev 118:989-1068 |
| Chiarella, Anna M; Wang, Tiffany A; Butler, Kyle V et al. (2018) Repressing Gene Transcription by Redirecting Cellular Machinery with Chemical Epigenetic Modifiers. J Vis Exp : |
| Wang, Dong-Yao; Kosowan, Joel; Samsom, James et al. (2018) Inhibition of the G9a/GLP histone methyltransferase complex modulates anxiety-related behavior in mice. Acta Pharmacol Sin 39:866-874 |
| Zhang, T; Wu, J; Ungvijanpunya, N et al. (2018) Smad6 Methylation Represses NF?B Activation and Periodontal Inflammation. J Dent Res 97:810-819 |
| Morini, Marco F; Giampietro, Costanza; Corada, Monica et al. (2018) VE-Cadherin-Mediated Epigenetic Regulation of Endothelial Gene Expression. Circ Res 122:231-245 |
| Butler, Kyle V; Chiarella, Anna M; Jin, Jian et al. (2018) Targeted Gene Repression Using Novel Bifunctional Molecules to Harness Endogenous Histone Deacetylation Activity. ACS Synth Biol 7:38-45 |
| Pellock, Samuel J; Creekmore, Benjamin C; Walton, William G et al. (2018) Gut Microbial ?-Glucuronidase Inhibition via Catalytic Cycle Interception. ACS Cent Sci 4:868-879 |
| Zhang, Chengwei; Han, Xiao-Ran; Yang, Xiaobao et al. (2018) Proteolysis Targeting Chimeras (PROTACs) of Anaplastic Lymphoma Kinase (ALK). Eur J Med Chem 151:304-314 |
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