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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...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2022
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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. |
format | Online Article Text |
id | pubmed-9136615 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
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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