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Development of Small-Molecules Targeting Receptor Activator of Nuclear Factor-kappa B Ligand (RANKL)-Receptor Activator of Nuclear Factor-kappa B (RANK) Protein-Protein Interaction by Structure-Based Virtual Screening and Hit Optimization

文献类型：期刊论文

作者Jiang, Min1; Peng, Lei2,3; Yang, Kai1; Wang, Tianqi1; Yan, Xueming1; Jiang, Tao1; Xu, Jianrong4; Qi, Jin1; Zhou, Hanbing1; Qian, Niandong1
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2019-06-13
卷号62期号:11页码:5370-5381
ISSN号0022-2623
DOI10.1021/acs.jmedchem.8b02027
通讯作者Xu, Xing(xuxing0510315@126.com) ; Deng, Lianfu(lfdeng@msn.com) ; Yang, Chunhao(chyang@simm.ac.cn)
英文摘要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.
WOS关键词OSTEOCLAST DIFFERENTIATION ; BONE-RESORPTION ; OSTEOPROTEGERIN ; DENOSUMAB ; PATHOGENESIS ; DISEASE ; CANCER ; WOMEN
资助项目NSFC[81703576] ; NSFC[81502902] ; Shanghai Municipal Health Bureau Scientific Research Project[201840185] ; Shanghai Municipal Health Bureau Scientific Research Project[20154Y0005] ; Committee of Science and Technology Young Scientific Research Foundation of Shanghai[16ZR1431900] ; Guangci Distinguished Young Scholars Training Program[GCQN-2017-A16] ; Guangci Distinguished Young Scholars Training Program[GCQN-2017-B22]
WOS研究方向Pharmacology & Pharmacy
语种英语
出版者AMER CHEMICAL SOC
WOS记录号WOS:000471834500009
源URL[http://119.78.100.183/handle/2S10ELR8/289543]  
专题新药研究国家重点实验室
通讯作者Xu, Xing; Deng, Lianfu; Yang, Chunhao
作者单位1.Shanghai Jiao Tong Univ, Shanghai Key Lab Bone & Joint Dis, Shanghai Ruijin Hosp, Shanghai Inst Traumatol & Orthopaed,Sch Med, 197 Second Ruijin Rd, Shanghai 200025, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, State Key Lab Drug Res, 555 Chong Zhi Rd, Shanghai 201203, Peoples R China
3.Univ Chinese Acad Sci, Sch Pharm, 19A Yuquan Rd, Beijing 100049, Peoples R China
4.Shanghai Jiao Tong Univ, Sch Med, Inst Med Sci, Dept Pharmacol & Chem Biol, 280 South Chongqing Rd, Shanghai 200025, Peoples R China
推荐引用方式
GB/T 7714		 Jiang, Min,Peng, Lei,Yang, Kai,et al. Development of Small-Molecules Targeting Receptor Activator of Nuclear Factor-kappa B Ligand (RANKL)-Receptor Activator of Nuclear Factor-kappa B (RANK) Protein-Protein Interaction by Structure-Based Virtual Screening and Hit Optimization[J]. JOURNAL OF MEDICINAL CHEMISTRY,2019,62(11):5370-5381.
APA Jiang, Min.,Peng, Lei.,Yang, Kai.,Wang, Tianqi.,Yan, Xueming.,...&Yang, Chunhao.(2019).Development of Small-Molecules Targeting Receptor Activator of Nuclear Factor-kappa B Ligand (RANKL)-Receptor Activator of Nuclear Factor-kappa B (RANK) Protein-Protein Interaction by Structure-Based Virtual Screening and Hit Optimization.JOURNAL OF MEDICINAL CHEMISTRY,62(11),5370-5381.
MLA Jiang, Min,et al."Development of Small-Molecules Targeting Receptor Activator of Nuclear Factor-kappa B Ligand (RANKL)-Receptor Activator of Nuclear Factor-kappa B (RANK) Protein-Protein Interaction by Structure-Based Virtual Screening and Hit Optimization".JOURNAL OF MEDICINAL CHEMISTRY 62.11(2019):5370-5381.

入库方式： OAI收割

来源：上海药物研究所

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