Ma, Junlong; Chen, Heng; Yang, Jie; Yu, Zutao; Huang, Pan; Yang, Haofeng; Zheng, Bifeng; Liu, Rangru; Li, Qianbin; Hu, Gaoyun; Chen, Zhuo published the artcile< Binding pocket-based design, synthesis and biological evaluation of novel selective BRD4-BD1 inhibitors>, Computed Properties of 21667-62-9 , the main research area is neoplasm antitumor BRD4 BD1; BD1 inhibitor; BRD4; Cancer; Computer-aided drug design; Fibrosis; Structure-activity relationship.
Bromodomain-containing protein 4 (BRD4), consisting of two tandem bromodomains (BD1 and BD2), is key epigenetic regulator in fibrosis and cancer, which has been reported that BD1 and BD2 have distinct roles in post-translational modification. But there are few selective inhibitors toward those two domains. Herein, this study designed and synthesized a series of novel selective BRD4-BD1 inhibitors, using computer-aided drug design (CADD) approach focused on exploring the difference of the binding pockets of BD1 and BD2, and finding the His437 a crucial way to achieve BRD4-BD1 selectivity. Our results revealed that the compound 3u(I) is a potent selective BRD4-BD1 inhibitor with IC50 values of 0.56 μM for BD1 but >100 μM for BD2. I exhibited a broad spectrum of anti-proliferative activity against several human cancer and fibroblastic cell lines, which might be related to its capability of reducing the expression of c-Myc and collagen I. Furthermore, I could induce apoptosis in A375 cells. To the contrary, the selective BD2 inhibitor, RVX-208, did not indicate any of these activities. Our findings highlight that the function of BRD4-BD1 might be predominant in fibrosis and cancer. And it is rational to further develop novel selective BRD4-BD1 inhibitors.
Bioorganic & Medicinal Chemistry published new progress about Antitumor agents. 21667-62-9 belongs to class nitriles-buliding-blocks, and the molecular formula is C9H6ClNO, Computed Properties of 21667-62-9 .
Referemce:
Nitrile – Wikipedia,
Nitriles – Chemistry LibreTexts