In 2013,Konze, Kyle D.; Ma, Anqi; Li, Fengling; Barsyte-Lovejoy, Dalia; Parton, Trevor; MacNevin, Christopher J.; Liu, Feng; Gao, Cen; Huang, Xi-Ping; Kuznetsova, Ekaterina; Rougie, Marie; Jiang, Alice; Pattenden, Samantha G.; Norris, Jacqueline L.; James, Lindsey I.; Roth, Bryan L.; Brown, Peter J.; Frye, Stephen V.; Arrowsmith, Cheryl H.; Hahn, Klaus M.; Wang, Gang Greg; Vedadi, Masoud; Jin, Jian published 《An Orally Bioavailable Chemical Probe of the Lysine Methyltransferases EZH2 and EZH1》.ACS Chemical Biology published the findings.Category: pyridine-derivatives The information in the text is summarized as follows:
EZH2 or EZH1 is the catalytic subunit of the polycomb repressive complex 2 that catalyzes methylation of histone H3 lysine 27 (H3K27). The trimethylation of H3K27 (H3K27me3) is a transcriptionally repressive post-translational modification. Overexpression of EZH2 and hypertrimethylation of H3K27 have been implicated in a number of cancers. Several selective inhibitors of EZH2 have been reported recently. Herein we disclose UNC1999, the first orally bioavailable inhibitor that has high in vitro potency for wild-type and mutant EZH2 as well as EZH1, a closely related H3K27 methyltransferase that shares 96% sequence identity with EZH2 in their resp. catalytic domains. UNC1999 was highly selective for EZH2 and EZH1 over a broad range of epigenetic and non-epigenetic targets, competitive with the cofactor SAM and non-competitive with the peptide substrate. This inhibitor potently reduced H3K27me3 levels in cells and selectively killed diffused large B cell lymphoma cell lines harboring the EZH2Y641N mutant. Importantly, UNC1999 was orally bioavailable in mice, making this inhibitor a valuable tool for investigating the role of EZH2 and EZH1 in chronic animal studies. We also designed and synthesized UNC2400, a close analog of UNC1999 with potency >1,000-fold lower than that of UNC1999 as a neg. control for cell-based studies. Finally, we created a biotin-tagged UNC1999 (UNC2399), which enriched EZH2 in pull-down studies, and a UNC1999-dye conjugate (UNC2239) for co-localization studies with EZH2 in live cells. Taken together, these compounds represent a set of useful tools for the biomedical community to investigate the role of EZH2 and EZH1 in health and disease. In the experiment, the researchers used 5-Bromo-2-chloropyridine(cas: 53939-30-3Category: pyridine-derivatives)
5-Bromo-2-chloropyridine(cas: 53939-30-3) belongs to pyridine. Pyridines form stable salts with strong acids. Pyridine itself is often used to neutralize acid formed in a reaction and as a basic solvent. Category: pyridine-derivatives