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.
ZL0420 is a potent and selective bromodomain-containing protein 4 (BRD4) inhibitor with IC50 values of 27 nM against BRD4 BD1 and 32 nM against BRD4 BD2.
PROTAC BET degrader-2 is a highly potent degrader of Bromodomain and Extra-Terminal (BET) proteins with an IC50 value of 9.6 nM in cell growth inhibition in the RS4;11 cells and capable of achieving tumor regression.
A1874 is a nutlin-based and BRD4-degrading PROTAC with a DC50 of 32 nM (induce BRD4 degradation in cells). Effective in inhibiting many cancer cell lines proliferation.
Curcumin (Turmeric yellow) is a natural phenolic compound with diverse pharmacologic effects including anti-inflammatory, antioxidant, antiproliferative and antiangiogenic activities. Curcumin is an inhibitor of p300 histone acetylatransferase (HATs) and also shows inhibitory effects on NF-κB and MAPKs.
ARV-771 is a potent bromodomain and extra-terminal (BET) proteins degrader based on PROTAC technology with Kd values of 4.7, 7.6, 7.6 nM against BRD2, BRD3 and BRD4, respectively.
BI 2536 is a dual PLK1 and BRD4 inhibitor with IC50s of 0.83 and 25 nM, respectively. BI-2536 suppresses IFNB (encoding IFN-β, interferon β) gene transcription.
