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ResearchIn-Press PreviewBone biologyTherapeutics Open Access | 10.1172/jci.insight.95042

Saracatinib is an efficacious clinical candidate for fibrodysplasia ossificans progressiva

Eleanor P. Williams,1 Jana Bagarova,2 Georgina Kerr,1 Dong-Dong Xia,2 Elsie S. Place,3 Devaveena Dey,2 Yue Shen,2 Geoffrey A. Bocobo,2 Agustin H. Mohedas,2 Xiuli Huang,4 Philip E. Sanderson,4 Arthur Lee,4 Wei Zheng,4 Aris N. Economides,5 James C. Smith,3 Paul B. Yu,2 and Alex N. Bullock1

1Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

2Department of Medicine, Harvard Medical School, Boston, United States of America

3Developmental Biology Laboratory, Francis Crick Institute, London, United Kingdom

4National Center for Advancing Translational Sciences, National Institutes of Health, NIH, Bethesda, United States of America

5Skeletal Diseases TFA Group, Regeneron Pharmaceuticals, Inc, Tarrytown, United States of America

Find articles by Williams, E. in: JCI | PubMed | Google Scholar |

1Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

2Department of Medicine, Harvard Medical School, Boston, United States of America

3Developmental Biology Laboratory, Francis Crick Institute, London, United Kingdom

4National Center for Advancing Translational Sciences, National Institutes of Health, NIH, Bethesda, United States of America

5Skeletal Diseases TFA Group, Regeneron Pharmaceuticals, Inc, Tarrytown, United States of America

Find articles by Bagarova, J. in: JCI | PubMed | Google Scholar

1Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

2Department of Medicine, Harvard Medical School, Boston, United States of America

3Developmental Biology Laboratory, Francis Crick Institute, London, United Kingdom

4National Center for Advancing Translational Sciences, National Institutes of Health, NIH, Bethesda, United States of America

5Skeletal Diseases TFA Group, Regeneron Pharmaceuticals, Inc, Tarrytown, United States of America

Find articles by Kerr, G. in: JCI | PubMed | Google Scholar

1Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

2Department of Medicine, Harvard Medical School, Boston, United States of America

3Developmental Biology Laboratory, Francis Crick Institute, London, United Kingdom

4National Center for Advancing Translational Sciences, National Institutes of Health, NIH, Bethesda, United States of America

5Skeletal Diseases TFA Group, Regeneron Pharmaceuticals, Inc, Tarrytown, United States of America

Find articles by Xia, D. in: JCI | PubMed | Google Scholar

1Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

2Department of Medicine, Harvard Medical School, Boston, United States of America

3Developmental Biology Laboratory, Francis Crick Institute, London, United Kingdom

4National Center for Advancing Translational Sciences, National Institutes of Health, NIH, Bethesda, United States of America

5Skeletal Diseases TFA Group, Regeneron Pharmaceuticals, Inc, Tarrytown, United States of America

Find articles by Place, E. in: JCI | PubMed | Google Scholar

1Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

2Department of Medicine, Harvard Medical School, Boston, United States of America

3Developmental Biology Laboratory, Francis Crick Institute, London, United Kingdom

4National Center for Advancing Translational Sciences, National Institutes of Health, NIH, Bethesda, United States of America

5Skeletal Diseases TFA Group, Regeneron Pharmaceuticals, Inc, Tarrytown, United States of America

Find articles by Dey, D. in: JCI | PubMed | Google Scholar

1Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

2Department of Medicine, Harvard Medical School, Boston, United States of America

3Developmental Biology Laboratory, Francis Crick Institute, London, United Kingdom

4National Center for Advancing Translational Sciences, National Institutes of Health, NIH, Bethesda, United States of America

5Skeletal Diseases TFA Group, Regeneron Pharmaceuticals, Inc, Tarrytown, United States of America

Find articles by Shen, Y. in: JCI | PubMed | Google Scholar

1Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

2Department of Medicine, Harvard Medical School, Boston, United States of America

3Developmental Biology Laboratory, Francis Crick Institute, London, United Kingdom

4National Center for Advancing Translational Sciences, National Institutes of Health, NIH, Bethesda, United States of America

5Skeletal Diseases TFA Group, Regeneron Pharmaceuticals, Inc, Tarrytown, United States of America

Find articles by Bocobo, G. in: JCI | PubMed | Google Scholar |

1Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

2Department of Medicine, Harvard Medical School, Boston, United States of America

3Developmental Biology Laboratory, Francis Crick Institute, London, United Kingdom

4National Center for Advancing Translational Sciences, National Institutes of Health, NIH, Bethesda, United States of America

5Skeletal Diseases TFA Group, Regeneron Pharmaceuticals, Inc, Tarrytown, United States of America

Find articles by Mohedas, A. in: JCI | PubMed | Google Scholar

1Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

2Department of Medicine, Harvard Medical School, Boston, United States of America

3Developmental Biology Laboratory, Francis Crick Institute, London, United Kingdom

4National Center for Advancing Translational Sciences, National Institutes of Health, NIH, Bethesda, United States of America

5Skeletal Diseases TFA Group, Regeneron Pharmaceuticals, Inc, Tarrytown, United States of America

Find articles by Huang, X. in: JCI | PubMed | Google Scholar

1Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

2Department of Medicine, Harvard Medical School, Boston, United States of America

3Developmental Biology Laboratory, Francis Crick Institute, London, United Kingdom

4National Center for Advancing Translational Sciences, National Institutes of Health, NIH, Bethesda, United States of America

5Skeletal Diseases TFA Group, Regeneron Pharmaceuticals, Inc, Tarrytown, United States of America

Find articles by Sanderson, P. in: JCI | PubMed | Google Scholar

1Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

2Department of Medicine, Harvard Medical School, Boston, United States of America

3Developmental Biology Laboratory, Francis Crick Institute, London, United Kingdom

4National Center for Advancing Translational Sciences, National Institutes of Health, NIH, Bethesda, United States of America

5Skeletal Diseases TFA Group, Regeneron Pharmaceuticals, Inc, Tarrytown, United States of America

Find articles by Lee, A. in: JCI | PubMed | Google Scholar

1Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

2Department of Medicine, Harvard Medical School, Boston, United States of America

3Developmental Biology Laboratory, Francis Crick Institute, London, United Kingdom

4National Center for Advancing Translational Sciences, National Institutes of Health, NIH, Bethesda, United States of America

5Skeletal Diseases TFA Group, Regeneron Pharmaceuticals, Inc, Tarrytown, United States of America

Find articles by Zheng, W. in: JCI | PubMed | Google Scholar |

1Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

2Department of Medicine, Harvard Medical School, Boston, United States of America

3Developmental Biology Laboratory, Francis Crick Institute, London, United Kingdom

4National Center for Advancing Translational Sciences, National Institutes of Health, NIH, Bethesda, United States of America

5Skeletal Diseases TFA Group, Regeneron Pharmaceuticals, Inc, Tarrytown, United States of America

Find articles by Economides, A. in: JCI | PubMed | Google Scholar |

1Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

2Department of Medicine, Harvard Medical School, Boston, United States of America

3Developmental Biology Laboratory, Francis Crick Institute, London, United Kingdom

4National Center for Advancing Translational Sciences, National Institutes of Health, NIH, Bethesda, United States of America

5Skeletal Diseases TFA Group, Regeneron Pharmaceuticals, Inc, Tarrytown, United States of America

Find articles by Smith, J. in: JCI | PubMed | Google Scholar |

1Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

2Department of Medicine, Harvard Medical School, Boston, United States of America

3Developmental Biology Laboratory, Francis Crick Institute, London, United Kingdom

4National Center for Advancing Translational Sciences, National Institutes of Health, NIH, Bethesda, United States of America

5Skeletal Diseases TFA Group, Regeneron Pharmaceuticals, Inc, Tarrytown, United States of America

Find articles by Yu, P. in: JCI | PubMed | Google Scholar |

1Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

2Department of Medicine, Harvard Medical School, Boston, United States of America

3Developmental Biology Laboratory, Francis Crick Institute, London, United Kingdom

4National Center for Advancing Translational Sciences, National Institutes of Health, NIH, Bethesda, United States of America

5Skeletal Diseases TFA Group, Regeneron Pharmaceuticals, Inc, Tarrytown, United States of America

Find articles by Bullock, A. in: JCI | PubMed | Google Scholar |

Published March 11, 2021 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.95042.
Copyright © 2021, Williams et al. 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/.
Published March 11, 2021 - Version history
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Abstract

Currently, no effective therapies exist for fibrodysplasia ossificans progressiva (FOP), a rare congenital syndrome in which heterotopic bone is formed in soft tissues due to dysregulated activity of the bone morphogenetic protein (BMP) receptor kinase ALK2/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/TGFb signaling pathway, and induced dorsalization in zebrafish embryos consistent with BMP antagonism. We further tested the efficacy of saracatinib using an inducible ACVR1Q207D transgenic mouse line, which provides a model of heterotopic ossification, as well as an inducible ACVR1R206H knock-in, which serves as a genetically and physiologically faithful model of FOP. In both models, saracatinib was well tolerated and potently inhibited the development of heterotopic ossification even when administered transiently following soft tissue injury. Together, these data suggest that saracatinib is an efficacious clinical candidate for repositioning in the treatment of FOP, offering an accelerated path to clinical proof of efficacy studies and potentially significant benefits to individuals with this devastating condition.

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