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Saracatinib is an efficacious clinical candidate for fibrodysplasia ossificans progressiva

DOI: 10.1172/jci.insight.95042 DOI Help

Authors: Eleanor Williams (University of Oxford) , Jana Bagarova (Harvard Medical School) , Georgina Kerr (University of Oxford) , Dong-Dong Xia (Harvard Medical School) , Elsie S. Place (Francis Crick Institute) , Devaveena Dey (Harvard Medical School) , Yue Shen (Harvard Medical School) , Geoffrey A. Bocobo (Harvard Medical School) , Agustin H. Mohedas (Harvard Medical School) , Xiuli Huang (National Center for Advancing Translational Sciences, NIH) , Philip E. Sanderson (National Center for Advancing Translational Sciences, NIH) , Arthur Lee (National Center for Advancing Translational Sciences, NIH) , Wei Zheng (National Center for Advancing Translational Sciences, NIH) , Aris N. Economides (Regeneron Pharmaceuticals Inc) , James C. Smith (Francis Crick Institute) , Paul B. Yu (Harvard Medical School) , Alex N. Bullock (University of Oxford)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Jci Insight , VOL 6

State: Published (Approved)
Published: March 2021
Diamond Proposal Number(s): 10619

Open Access Open Access

Abstract: 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 ACVR1Q207D-transgenic mouse line, which provides a model of heterotopic ossification (HO), as well as an inducible ACVR1R206H-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.

Diamond Keywords: Fibrodysplasia Ossificans Progressiva

Subject Areas: Biology and Bio-materials, Medicine

Instruments: I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 31/05/2021 10:34


Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)