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.
|Wagner, Tobias; Greschik, Holger; Burgahn, Teresa et al. (2016) Identification of a small-molecule ligand of the epigenetic reader protein Spindlin1 via a versatile screening platform. Nucleic Acids Res 44:e88|
|Butler, Kyle V; Ma, Anqi; Yu, Wenyu et al. (2016) Structure-Based Design of a Covalent Inhibitor of the SET Domain-Containing Protein 8 (SETD8) Lysine Methyltransferase. J Med Chem 59:9881-9889|
|Shen, Yudao; Szewczyk, Magdalena M; Eram, Mohammad S et al. (2016) Discovery of a Potent, Selective, and Cell-Active Dual Inhibitor of Protein Arginine Methyltransferase 4 and Protein Arginine Methyltransferase 6. J Med Chem 59:9124-9139|
|Agarwal, Prasoon; Alzrigat, Mohammad; PÃ¡rraga, Alba Atienza et al. (2016) Genome-wide profiling of histone H3 lysine 27 and lysine 4 trimethylation in multiple myeloma reveals the importance of Polycomb gene targeting and highlights EZH2 as a potential therapeutic target. Oncotarget 7:6809-23|
|Yang, Xiaobao; Li, Fengling; Konze, Kyle D et al. (2016) Structure-Activity Relationship Studies for Enhancer of Zeste Homologue 2 (EZH2) and Enhancer of Zeste Homologue 1 (EZH1) Inhibitors. J Med Chem 59:7617-33|
|Butler, Kyle V; Bohn, Kelsey; Hrycyna, Christine A et al. (2016) Non-Substrate Based, Small Molecule Inhibitors of the Human Isoprenylcysteine Carboxyl Methyltransferase. Medchemcomm 7:1016-1021|
|Eram, Mohammad S; Shen, Yudao; Szewczyk, Magdalena M et al. (2016) A Potent, Selective, and Cell-Active Inhibitor of Human Type I Protein Arginine Methyltransferases. ACS Chem Biol 11:772-81|
|Kaniskan, H Ãœmit; Jin, Jian (2015) Chemical probes of histone lysine methyltransferases. ACS Chem Biol 10:40-50|
|Wang, Li; Xie, Ling; Ramachandran, Srinivas et al. (2015) Non-canonical Bromodomain within DNA-PKcs Promotes DNA Damage Response and Radioresistance through Recognizing an IR-Induced Acetyl-Lysine on H2AX. Chem Biol 22:849-61|
|Kaniskan, H Ãœmit; Konze, Kyle D; Jin, Jian (2015) Selective inhibitors of protein methyltransferases. J Med Chem 58:1596-629|
Showing the most recent 10 out of 29 publications