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Drug discovery of sclerostin inhibitors

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...

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Autores principales: Yu, Sifan, Li, Dijie, Zhang, Ning, Ni, Shuaijian, Sun, Meiheng, Wang, Luyao, Xiao, Huan, Liu, Dingdong, Liu, Jin, Yu, Yuanyuan, Zhang, Zongkang, Yeung, Samuel Tin Yui, Zhang, Shu, Lu, Aiping, Zhang, Zhenlin, Zhang, Baoting, Zhang, Ge
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9136615/
https://www.ncbi.nlm.nih.gov/pubmed/35646527
http://dx.doi.org/10.1016/j.apsb.2022.01.012
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author Yu, Sifan
Li, Dijie
Zhang, Ning
Ni, Shuaijian
Sun, Meiheng
Wang, Luyao
Xiao, Huan
Liu, Dingdong
Liu, Jin
Yu, Yuanyuan
Zhang, Zongkang
Yeung, Samuel Tin Yui
Zhang, Shu
Lu, Aiping
Zhang, Zhenlin
Zhang, Baoting
Zhang, Ge
author_facet Yu, Sifan
Li, Dijie
Zhang, Ning
Ni, Shuaijian
Sun, Meiheng
Wang, Luyao
Xiao, Huan
Liu, Dingdong
Liu, Jin
Yu, Yuanyuan
Zhang, Zongkang
Yeung, Samuel Tin Yui
Zhang, Shu
Lu, Aiping
Zhang, Zhenlin
Zhang, Baoting
Zhang, Ge
author_sort Yu, Sifan
collection PubMed
description 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.
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spelling pubmed-91366152022-05-28 Drug discovery of sclerostin inhibitors Yu, Sifan Li, Dijie Zhang, Ning Ni, Shuaijian Sun, Meiheng Wang, Luyao Xiao, Huan Liu, Dingdong Liu, Jin Yu, Yuanyuan Zhang, Zongkang Yeung, Samuel Tin Yui Zhang, Shu Lu, Aiping Zhang, Zhenlin Zhang, Baoting Zhang, Ge Acta Pharm Sin B Review 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. Elsevier 2022-05 2022-01-21 /pmc/articles/PMC9136615/ /pubmed/35646527 http://dx.doi.org/10.1016/j.apsb.2022.01.012 Text en © 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Review
Yu, Sifan
Li, Dijie
Zhang, Ning
Ni, Shuaijian
Sun, Meiheng
Wang, Luyao
Xiao, Huan
Liu, Dingdong
Liu, Jin
Yu, Yuanyuan
Zhang, Zongkang
Yeung, Samuel Tin Yui
Zhang, Shu
Lu, Aiping
Zhang, Zhenlin
Zhang, Baoting
Zhang, Ge
Drug discovery of sclerostin inhibitors
title Drug discovery of sclerostin inhibitors
title_full Drug discovery of sclerostin inhibitors
title_fullStr Drug discovery of sclerostin inhibitors
title_full_unstemmed Drug discovery of sclerostin inhibitors
title_short Drug discovery of sclerostin inhibitors
title_sort drug discovery of sclerostin inhibitors
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9136615/
https://www.ncbi.nlm.nih.gov/pubmed/35646527
http://dx.doi.org/10.1016/j.apsb.2022.01.012
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