Epigenetic regulators of gene expression and chromatin state include so-called writers, erasers, and readers of chromatin modifications.Well-characterized examples of reader domains include bromodomains typically binding acetyllysine and chromatin organization modifier (chromo), malignant brain tumor (MBT), plant homeodomain (PHD), and Tudor domains generally associating with methyllysine. Research on epigenetic readers has been tremendously influenced by the discovery of selective inhibitors targeting the bromodomain and extraterminal motif (BET) family of acetyl-lysine readers. The human genome encodes 46 proteins containing 61 bromodomains clustered into eight families. Distinct experimental approaches are used to identify the first BET inhibitors, GSK 525762A and (+)-JQ-1.
The Polycomb group (PcG) protein, enhancer of zeste homologue 2 (EZH2), has an essential role in promoting histone H3 lysine 27 trimethylation (H3K27me3) and epigenetic gene silencing. This function of EZH2 is important for cell proliferation and inhibition of cell differentiation, and is implicated in cancer progression. Cyclin-dependent kinases regulate epigenetic gene silencing through phosphorylation of EZH2. In many types of cancers including lymphomas and leukemia, EZH2 is postulated to exert its oncogenic effects via aberrant histone and DNA methylation, causing silencing of tumor suppressor genes.
p300/CBP is not only a transcriptional adaptor but also a histone acetyltransferase.
KU-57788 is a potent and selective inhibitor of DNA-PK, a modest inhibitor of BRD4 and BRDT, with IC50s of 13 nM, 1 μM and 3.5 μM, respectively, and also increases CRISPR/Cas9-mediated editing frequencies.
TG-101348 is a selective inhibitor of JAK2 with IC50 of 3 nM, 35- and 334-fold more selective for JAK2 versus JAK1 and JAK3, and also inhibits BRD4 with IC50 of 340 nM.
