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

被引：22

作者：

Jiang, Min ^{[1
]}

Peng, Lei ^{[2
,3
]}

Yang, Kai ^{[1
]}

Wang, Tianqi ^{[1
]}

Yan, Xueming ^{[1
]}

Jiang, Tao ^{[1
]}

Xu, Jianrong ^{[4
]}

Qi, Jin ^{[1
]}

Zhou, Hanbing ^{[1
]}

Qian, Niandong ^{[1
]}

Zhou, Qi ^{[1
]}

Chen, Bo ^{[1
]}

Xu, Xing ^{[1
]}

Deng, Lianfu ^{[1
]}

Yang, Chunhao ^{[2
,3
]}

机构：

[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

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2019年 / 62卷 / 11期

关键词：

OSTEOCLAST DIFFERENTIATION; BONE-RESORPTION; OSTEOPROTEGERIN; DENOSUMAB; PATHOGENESIS; DISEASE; CANCER; WOMEN;

D O I：

10.1021/acs.jmedchem.8b02027

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

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.

引用

页码：5370 / 5381

页数：12

共 39 条

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