期刊
JCI INSIGHT
卷 6, 期 8, 页码 -出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/jci.insight.95042
关键词
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资金
- NIH [AR057374, HL007604]
- Department of Defense [MR140072]
- Harvard Stem Cell Institute Seed Award
- Leducq Foundation Transatlantic Network of Excellence Award
- Francis Crick Institute
- Cancer Research UK [FC001-157]
- UK Medical Research Council [FC001-157]
- Wellcome [FC001-157, 106169/ZZ14/Z]
- Howard Hughes Medical Institute Early Career Physician-Scientist Award
- International FOP Association
- SGC [1097737]
- AbbVie
- Bayer Pharma AG
- Boehringer Ingelheim
- Canada Foundation for Innovation
- Eshelman Institute for Innovation
- Genentech
- Genome Canada through Ontario Genomics Institute [OGI-196]
- EU/EFPIA/OICR/McGill/KTH/Diamond Innovative Medicines Initiative 2 Joint Undertaking [875510]
- Janssen
- Merck Co.
- MSD
- Novartis Pharma AG
- Pfizer
- Sao Paulo Research Foundation-FAPESP
- Takeda
- Innovative Medicines Initiative 2 Joint Undertaking (STOPFOP) [821600]
Saracatinib, identified as a potent ALK2 kinase inhibitor, demonstrated efficacy in inhibiting heterotopic ossification in FOP models, offering accelerated path to clinical proof-of-efficacy studies and potentially significant benefits to individuals with this condition.
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-beta 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.
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