Multicellular organisms have evolved elaborate mechanisms to enable the differential and cell-type specific expression of genes. This capability permits specialization of function between cells even though each cell contains essentially the same genetic code. Epigenetics refers to these heritable changes in how the genome is accessed in different cell-types and during development and differentiation. The template upon which the epigenome is written is chromatin - the complex of histone proteins, RNA and DNA that efficiently package the genome in an appropriately accessible state within each cell. The state of chromatin, and therefore access to the genetic code, is largely regulated by specific chemical modifications to histone proteins and DNA, and the recognition of these marks by other proteins and protein complexes. These modifications include but not limited to: histone lysine and arginine methylation, lysine acetylation, and DNA methylation. Given the wide-spread importance of chromatin regulation to cell biology, the enzymes which produce these modifications (the 'writers'), the proteins that recognize them (the 'readers'), and the enzymes that remove them (the 'erasers') are critical targets for manipulation in order to further understand the histone code and its role in human disease. Among the 'writers', closely related lysine methyltransferases G9a and GLP modulate the transcriptional repression of a variety of genes via dimethylation of histone H3 lysine 9 as well as dimethylation of non-histone proteins. G9a and GLP have been implicated in many human conditions including drug addiction, leukemia, and HIV-1 latency. Despite the importance of G9a/GLP in human diseases, no G9a/GLP in vivo chemical probes have been created. We recently discovered the first G9a/GLP cellular chemical probe UNC0638, which has high potency and selectivity, robust on-target activities in cells, and low cell toxicity. However, UNC0638 is not suitable for animal studies due to its poor pharmacokinetic parameters. In addition, we developed innovative biochemical assays, cellular assays, and animal models for evaluating G9a/GLP inhibitors. We also discovered the first cofactor-competitive non-nucleoside inhibitors of G9a as structurally distinct back-up series. In this project, we propose to: (1) optimize the UNC0638 series into G9a/GLP chemical probes that are suitable for in vivo studies;(2) demonstrate utilities of the resulting G9a/GLP in vivo probes in drug addiction, leukemia, and HIV-1 latency animal models;(3) in parallel, optimize our recently discovered G9a inhibitor back-up series. Successful completion of this project will yield the first G9a/GLP in vivo chemical probes that will be extremely valuable tools for investigating diverse, critical functions of G9a/GLP and assessing their potential as therapeutic targets.
Lysine methyltransferases G9a and GLP modulate the transcriptional repression of a variety of genes via dimethylation of histone H3 lysine 9 as well as dimethylation of non-histone proteins. G9a and GLP have been implicated in many human conditions including drug addiction, leukemia, and HIV-1 latency. In this project, we propose to create the first G9a/GLP in vivo chemical probes that will be extremely valuable tools for investigating diverse, critical functions of G9a/GLP and assessing their potential as therapeutic targets.
|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|
|Xiong, Yan; Li, Fengling; Babault, Nicolas et al. (2017) Structure-activity relationship studies of G9a-like protein (GLP) inhibitors. Bioorg Med Chem 25:4414-4423|
|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|
|Alzrigat, Mohammad; Jernberg-Wiklund, Helena (2017) The miR-125a and miR-320c are potential tumor suppressor microRNAs epigenetically silenced by the polycomb repressive complex 2 in multiple myeloma. RNA Dis 4:|
|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|
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