Drug discovery of sclerostin inhibitors

Acta Pharmaceutica Sinica B

Shuaijian Ni¹  Zongkang Zhang¹  Dijie Li¹  Aiping Lu¹  Dingdong Liu¹  Meiheng Sun²  Zhenlin Zhang²  Jin Liu²  Samuel Tin Yui Yeung²  Ge Zhang³  Huan Xiao³  Shu Zhang³  Ning Zhang³  Yuanyuan Yu³  Sifan Yu³  Luyao Wang⁴  Baoting Zhang⁴ 

[1] Institute of Integrated Bioinfomedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tsai, Hong Kong 999077, China;Institute of Precision Medicine and Innovative Drug Discovery, HKBU Institute for Research and Continuing Education, Shenzhen 518000, China;Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tsai, Hong Kong 999077, China;School of Chinese Medicine, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong 999077, China;

关键词: Sclerostin;    WNT signalling pathway;    Sclerostin inhibitors;    Antibody;    Bone diseases;    Aptamer;   

DOI  :  

来源: DOAJ

【 摘 要 】

Sclerostin, a protein secreted from osteocytes, negatively regulates the WNT signaling pathway by binding to the LRP5/6 co-receptors and further inhibits bone formation and promotes bone resorption. Sclerostin contributes to musculoskeletal system-related diseases, making it a promising therapeutic target for the treatment of WNT-related bone diseases. Additionally, emerging evidence indicates that sclerostin contributes to the development of cancers, obesity, and diabetes, suggesting that it may be a promising therapeutic target for these diseases. Notably, cardiovascular diseases are related to the protective role of sclerostin. In this review, we summarize three distinct types of inhibitors targeting sclerostin, monoclonal antibodies, aptamers, and small-molecule inhibitors, from which monoclonal antibodies have been developed. As the first-in-class sclerostin inhibitor approved by the U.S. FDA, the monoclonal antibody romosozumab has demonstrated excellent effectiveness in the treatment of postmenopausal osteoporosis; however, it conferred high cardiovascular risk in clinical trials. Furthermore, romosozumab could only be administered by injection, which may cause compliance issues for patients who prefer oral therapy. Considering these above safety and compliance concerns, we therefore present relevant discussion and offer perspectives on the development of next-generation sclerostin inhibitors by following several ways, such as concomitant medication, artificial intelligence-based strategy, druggable modification, and bispecific inhibitors strategy.

【 授权许可】

Unknown