Drug discovery of sclerostin inhibitors

Sifan Yu, Dijie Li, Ning Zhang, Shuaijian Ni, Meiheng Sun, Luyao Wang, Huan Xiao, Dingdong Liu, Jin Liu, Yuanyuan Yu, Zongkang Zhang, Samuel Tin Yui Yeung, Shu Zhang, Aiping Lu, Zhenlin Zhang*, Baoting Zhang*, Ge Zhang*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

16 Citations (Scopus)


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.
Original languageEnglish
Pages (from-to)2150-2170
Number of pages21
JournalActa Pharmaceutica Sinica B
Issue number5
Publication statusPublished - May 2022

Scopus Subject Areas

  • Pharmacology, Toxicology and Pharmaceutics(all)

User-Defined Keywords

  • Antibody
  • Aptamer
  • Artificial intelligence
  • Bone diseases
  • Sclerostin
  • Sclerostin inhibitors
  • Small molecule inhibitors
  • WNT signalling pathway


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