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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Synthetic and Biological Chemistry B Study Section (SBCB)
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Fabian, Miles
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Icahn School of Medicine at Mount Sinai
Schools of Medicine
New York
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Butler, Kyle V; MacDonald, Ian A; Hathaway, Nathaniel A et al. (2017) Report and Application of a Tool Compound Data Set. J Chem Inf Model 57:2699-2706
Alzrigat, Mohammad; Párraga, Alba Atienza; Agarwal, Prasoon et al. (2017) EZH2 inhibition in multiple myeloma downregulates myeloma associated oncogenes and upregulates microRNAs with potential tumor suppressor functions. Oncotarget 8:10213-10224
Rizq, Ola; Mimura, Naoya; Oshima, Motohiko et al. (2017) Dual Inhibition of EZH2 and EZH1 Sensitizes PRC2-Dependent Tumors to Proteasome Inhibition. Clin Cancer Res 23:4817-4830
Huang, Qingrong; He, Shan; Tian, Yuanyuan et al. (2017) Hsp90 inhibition destabilizes Ezh2 protein in alloreactive T cells and reduces graft-versus-host disease in mice. Blood 129:2737-2748
Veschi, Veronica; Liu, Zhihui; Voss, Ty C et al. (2017) Epigenetic siRNA and Chemical Screens Identify SETD8 Inhibition as a Therapeutic Strategy for p53 Activation in High-Risk Neuroblastoma. Cancer Cell 31:50-63
Kaniskan, H Ümit; Jin, Jian (2017) Recent progress in developing selective inhibitors of protein methyltransferases. Curr Opin Chem Biol 39:100-108
Kim, Yuna; Lee, Hyeong-Min; Xiong, Yan et al. (2017) Targeting the histone methyltransferase G9a activates imprinted genes and improves survival of a mouse model of Prader-Willi syndrome. Nat Med 23:213-222
Kaniskan, H Ümit; Martini, Michael L; Jin, Jian (2017) Inhibitors of Protein Methyltransferases and Demethylases. Chem Rev :
Xiong, Yan; Li, Fengling; Babault, Nicolas et al. (2017) Discovery of Potent and Selective Inhibitors for G9a-Like Protein (GLP) Lysine Methyltransferase. J Med Chem 60:1876-1891
Jain, Rinku; Butler, Kyle V; Coloma, Javier et al. (2017) Development of a S-adenosylmethionine analog that intrudes the RNA-cap binding site of Zika methyltransferase. Sci Rep 7:1632

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