Brominedomain can recognize acetylated lysine residues. As the “reader” of lysine acetylation, the bromine domain is responsible for the transduction of signals carried by acetylated lysine residues and transforming them into various normal or abnormal phenotypes. Specifically, the bromine domain-containing proteins have a variety of functions. Besides, it ranges from histone acetyltransferase activity and chromatin remodeling to transcription-mediated and CO activation. BET proteins are epigenetic readers. Moreover, they are identified and immobilized on acetyl-lysine by tandem bromine domain (BRD) modules. Small molecule inhibitors of bromodomain (BET) family proteins are promising options for cancer treatment. Furthermore, BET inhibitors have shown significant efficacy in preclinical models. NHWD-870 is a potent, orally active, and selective BET family bromodomain inhibitor.
NHWD-870 is a potent, orally active, and selective BET family bromodomain inhibitor.
Firstly, NHWD-870 only binds bromodomains of BRD2, BRD3, BRD4 (IC50=2.7 nM), and BRDT. Meanwhile, NHWD-870 has potent tumor-suppressive efficacies and suppresses cancer cell-macrophage interaction. Nonetheless, NHWD-870 increases tumor apoptosis and inhibits tumor proliferation.
In the second place, NHWD-870 inhibits melanoma A375 cells with an IC50 of 2.46 nM. NHWD-870 with 0-50 nM for 24 hours inhibits BRD4 phosphorylation and c-MYC expression. Additionally, NHWD-870 exhibits mild inhibition of the hERG channel (IC50=5.4 µM). NHWD-870 shows robust activities inducing apoptosis and suppressing cell proliferation.
Last but not the least, NHWD-870 reduces the number of tumor-associated macrophages (TAMs) in subcutaneously implanted H526 and A2780 tumors. Particularly, NHWD-870 downregulated CSF1 expression in tumor cells to inhibit TAM proliferation. NHWD-870 has potent antitumor efficacies in xenograft mouse models of small cell lung cancer, triple-negative breast cancer, and ovarian cancer.
Obviously, NHWD-870 manifests diverse mechanisms of action in different cancer settings. In particular, NHWD-870 inhibits tumor cell growth by downregulating the PDGFRβ, MEK1/2, and STAT1/MYC signaling in tumor cells. At the same time, NHWD-870 inhibits tumor angiogenesis by decreasing PDGF production in tumor cells. NHWD-870 decreases the PDGFRβ and MEK1/2 signaling in endothelial cells.
All in all, NHWD-870 is a potent, orally active, and selective BET family bromodomain inhibitor.