A Bromodomain (BRD) is a protein domain of about 110 amino acids and is a “reader” of lysine acetylation. Specifically, BRDs recognize acetylated lysine residues, such as those on the N-terminal tail of histones. Besides, BRD is responsible for the transduction of signals carried by acetylated lysine residues and transforming them into various normal or abnormal phenotypes. Moreover, BRDs specifically bind to different acetyl-lysine sites in histone and non-histone proteins. BRDs have become a promising therapeutic target for human diseases such as cancer.
CECR2 contains a single BRD. Furthermore, the gene encoding CECR2 is located on chromosome 22q11 and repeats in cat’s eye syndrome. Studies have shown that CECR2 is relevant to neuronal and chromatin remodeling and DNA damage response. Today, we will introduce an eye syndrome chromosome region, candidate 2 (CECR2) BRD inhibitor, NVS-CECR2-1.
NVS-CECR2-1 is a selective CECR2 BRD (non-BET family) inhibitor.
First of all, NVS-CECR2-1 is a non-BET family Bromodomain (BRD) inhibitor. Meanwhile, NVS-CECR2-1 binds to CECR2 BRD with high affinity (IC50=47 nM; KD=80 nM). NVS-CECR2-1 exhibits cytotoxic activity and induces apoptosis against various cancer cells by targeting CECR2 as well as via the CECR2-independent mechanism.
In the second place, NVS-CECR2-1 with 1-4 μM for 72 hours decreased the viability of cancer cells analyzed in a dose-dependent manner. Nonetheless, NVS-CECR2-1 increased apoptosis in a dose-dependent manner, with more than 80% of cells undergoing apoptosis at 6 μM. Particularly, NVS-CECR2-1 had virtually no effect on necrosis.
Obviously, NVS-CECR2-1 inhibits chromatin binding of CECR2 BRD within SW48 cells. Interestingly, NVS-CECR2-1 dissociates CECR2 from chromatin in a dose-dependent manner without affecting BRG1. In particular, NVS-CECR2-1 inhibits the clonogenic ability of SW48 cells in a dose-dependent manner, and its IC50 value is estimated to be 0.64 μM. Additionally, NVS-CECR2-1 inhibits chromatin binding of CECR2 BRD and displaces CECR2 from chromatin within cells.
All in all, NVS-CECR2-1 is a selective CECR2 BRD (non-BET family) inhibitor.