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Saracatinib is an efficacious clinical candidate for fibrodysplasia ossificans progressiva
Currently, no effective therapies exist for fibrodysplasia ossificans progressiva (FOP), a rare congenital syndrome in which heterotopic bone is formed in soft tissues owing to dysregulated activity of the bone morphogenetic protein (BMP) receptor kinase ALK2 (also known as ACVR1). From a screen of...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Clinical Investigation
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8119212/ https://www.ncbi.nlm.nih.gov/pubmed/33705358 http://dx.doi.org/10.1172/jci.insight.95042 |
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author | Williams, Eleanor Bagarova, Jana Kerr, Georgina Xia, Dong-Dong Place, Elsie S. Dey, Devaveena Shen, Yue Bocobo, Geoffrey A. Mohedas, Agustin H. Huang, Xiuli Sanderson, Philip E. Lee, Arthur Zheng, Wei Economides, Aris N. Smith, James C. Yu, Paul B. Bullock, Alex N. |
author_facet | Williams, Eleanor Bagarova, Jana Kerr, Georgina Xia, Dong-Dong Place, Elsie S. Dey, Devaveena Shen, Yue Bocobo, Geoffrey A. Mohedas, Agustin H. Huang, Xiuli Sanderson, Philip E. Lee, Arthur Zheng, Wei Economides, Aris N. Smith, James C. Yu, Paul B. Bullock, Alex N. |
author_sort | Williams, Eleanor |
collection | PubMed |
description | Currently, no effective therapies exist for fibrodysplasia ossificans progressiva (FOP), a rare congenital syndrome in which heterotopic bone is formed in soft tissues owing to dysregulated activity of the bone morphogenetic protein (BMP) receptor kinase ALK2 (also known as ACVR1). From a screen of known biologically active compounds, we identified saracatinib as a potent ALK2 kinase inhibitor. In enzymatic and cell-based assays, saracatinib preferentially inhibited ALK2, compared with other receptors of the BMP/TGF-β signaling pathway, and induced dorsalization in zebrafish embryos consistent with BMP antagonism. We further tested the efficacy of saracatinib using an inducible ACVR1(Q207D)-transgenic mouse line, which provides a model of heterotopic ossification (HO), as well as an inducible ACVR1(R206H)-knockin mouse, which serves as a genetically and physiologically faithful FOP model. In both models, saracatinib was well tolerated and potently inhibited the development of HO, even when administered transiently following soft tissue injury. Together, these data suggest that saracatinib is an efficacious clinical candidate for repositioning in FOP treatment, offering an accelerated path to clinical proof-of-efficacy studies and potentially significant benefits to individuals with this devastating condition. |
format | Online Article Text |
id | pubmed-8119212 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Society for Clinical Investigation |
record_format | MEDLINE/PubMed |
spelling | pubmed-81192122021-05-21 Saracatinib is an efficacious clinical candidate for fibrodysplasia ossificans progressiva Williams, Eleanor Bagarova, Jana Kerr, Georgina Xia, Dong-Dong Place, Elsie S. Dey, Devaveena Shen, Yue Bocobo, Geoffrey A. Mohedas, Agustin H. Huang, Xiuli Sanderson, Philip E. Lee, Arthur Zheng, Wei Economides, Aris N. Smith, James C. Yu, Paul B. Bullock, Alex N. JCI Insight Research Article Currently, no effective therapies exist for fibrodysplasia ossificans progressiva (FOP), a rare congenital syndrome in which heterotopic bone is formed in soft tissues owing to dysregulated activity of the bone morphogenetic protein (BMP) receptor kinase ALK2 (also known as ACVR1). From a screen of known biologically active compounds, we identified saracatinib as a potent ALK2 kinase inhibitor. In enzymatic and cell-based assays, saracatinib preferentially inhibited ALK2, compared with other receptors of the BMP/TGF-β signaling pathway, and induced dorsalization in zebrafish embryos consistent with BMP antagonism. We further tested the efficacy of saracatinib using an inducible ACVR1(Q207D)-transgenic mouse line, which provides a model of heterotopic ossification (HO), as well as an inducible ACVR1(R206H)-knockin mouse, which serves as a genetically and physiologically faithful FOP model. In both models, saracatinib was well tolerated and potently inhibited the development of HO, even when administered transiently following soft tissue injury. Together, these data suggest that saracatinib is an efficacious clinical candidate for repositioning in FOP treatment, offering an accelerated path to clinical proof-of-efficacy studies and potentially significant benefits to individuals with this devastating condition. American Society for Clinical Investigation 2021-04-22 /pmc/articles/PMC8119212/ /pubmed/33705358 http://dx.doi.org/10.1172/jci.insight.95042 Text en © 2021 Williams et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Article Williams, Eleanor Bagarova, Jana Kerr, Georgina Xia, Dong-Dong Place, Elsie S. Dey, Devaveena Shen, Yue Bocobo, Geoffrey A. Mohedas, Agustin H. Huang, Xiuli Sanderson, Philip E. Lee, Arthur Zheng, Wei Economides, Aris N. Smith, James C. Yu, Paul B. Bullock, Alex N. Saracatinib is an efficacious clinical candidate for fibrodysplasia ossificans progressiva |
title | Saracatinib is an efficacious clinical candidate for fibrodysplasia ossificans progressiva |
title_full | Saracatinib is an efficacious clinical candidate for fibrodysplasia ossificans progressiva |
title_fullStr | Saracatinib is an efficacious clinical candidate for fibrodysplasia ossificans progressiva |
title_full_unstemmed | Saracatinib is an efficacious clinical candidate for fibrodysplasia ossificans progressiva |
title_short | Saracatinib is an efficacious clinical candidate for fibrodysplasia ossificans progressiva |
title_sort | saracatinib is an efficacious clinical candidate for fibrodysplasia ossificans progressiva |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8119212/ https://www.ncbi.nlm.nih.gov/pubmed/33705358 http://dx.doi.org/10.1172/jci.insight.95042 |
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