兰克尔
德诺苏马布
化学
秩配基
激活剂(遗传学)
破骨细胞
骨吸收
受体
小分子
骨保护素
虚拟筛选
癌症研究
药理学
药物发现
生物化学
骨质疏松症
内科学
医学
作者
Min Jiang,Peng Lei,Kai Yang,Tianqi Wang,Xueming Yan,Tao Jiang,Jianrong Xu,Jin Qi,Hanbing Zhou,Nan Qian,Qi Zhou,Bin Chen,Xing Xu,Lianfu Deng,Chunhao Yang
标识
DOI:10.1021/acs.jmedchem.8b02027
摘要
Targeting RANKL/RANK offers the possibility of developing novel therapeutic approaches to treat bone metabolic diseases. Multiple efforts have been made to inhibit RANKL. For example, marketed monoclonal antibody drug Denosumab could inhibit the maturation of osteoclasts by binding to RANKL. This study is an original approach aimed at discovering small-molecule inhibitors impeding RANKL/RANK protein interaction. We identified compound 34 as a potent and selective RANKL/RANK inhibitor by performing structure-based virtual screening and hit optimization. Disruption of the RANKL/RANK interaction by 34 effectively inhibits RANKL-induced osteoclastogenesis and bone resorption. The expression of osteoclast marker genes was also suppressed by treatment of 34. Furthermore, 34 markedly blocked the NFATc1/c-fos pathway. Thus, our current work demonstrates that the chemical tractability of the difficult PPI (RANKL/RANK) target by a small-molecule compound 34 offers a potential lead compound to facilitate the development of new medications for bone-related diseases.
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