5/7/2023 0 Comments Protein scaffold inhibitor![]() For this reason, many studies have been conducted to develop potent bromodomain inhibitors ( 10). Subsequent studies demonstrated that most of the leukemic and lymphoma cells die by brd4 inhibition ( 9). In addition, brd4 knockdown in AML cell lines causes downregulation of c-myc expression as to induce cell death ( 8). As knockdown of BRD4-NUT in NMC caused significant decrease in BRD4-NUT positive cell proliferation ( 7), brd4 has been highlighted as a powerful therapeutic target for NMC. NUT gene, which is located on chromosome 15q14, is fused with BRD4 or BRD3, creating BRD4-NUT fusion proteins. Among them, brd4, one of the BET (bromodmain and extra-terminal proteins) proteins, was revealed to play a crucial role in NUT midline carcinoma (NMC) ( 6). In the human genome, there are 46 bromodomain-containing proteins, many of which are HATs, HAT-associated proteins, helicases, ATP-dependent chromatin remodeling complexes, transcriptional coactivators, and nuclear scaffolding proteins. In 1992, bromodomain, a protein module containing approximately 110 amino acids, was identified as a lysine acetylation reader in Drosophila melanogaster study ( 5). Bromodomain is one of the best known modules to recognize and bind to acetylated histones ( 4). For this acetylation to be involved in gene expression, we need a ‘reader’ to recognize acetylated histone. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) functions as ‘writers’ and ‘erasers’ respectively by controlling acetyl mark of histone lysine residue ( 3). In epigenetics, lysine acetylation has been considered as a key step of post-translational modifications ( 1, 2). In conclusion, the novel scaffold to suppress brd4 activity was effective against cancer cells both in vitro and in vivo. In addition, the compounds exhibited cytotoxic effects against gastric cancer cell lines which were resistant to I-BET-762, a BET bromodomain inhibitor. A10, one of the compounds with naphthalene-1,4-dione scaffold, also exhibited tumor growth inhibition effects in the xenograft assay. The compounds with naphthalene-1,4-dione had cytotoxic effects against the Ty82 cell line, a NUT midline carcinoma cell line, whose proliferation is dependent on brd4 activity. As a result, it was revealed that compounds having naphthalene-1,4-dione scaffold inhibited the binding of bromodomain to acetylated histone. Furthermore, cell cytotoxicity and xenograft assays were performed to examine if the compound was effective both in vitro and in vivo. Mid-throughput screening against brd4 bromodomain was performed using alpha-screen and homogeneous time-resolved fluorescence assays. The present study provided a novel chemical scaffold which inhibited brd4 activity. Since bromodomain containing 4 (brd4) has been considered as a prominent cancer target, numerous attempts have been made to develop potent brd4 bromodomain inhibitors.
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