{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T20:08:18Z","timestamp":1789416498998,"version":"build-2803163510"},"reference-count":42,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T00:00:00Z","timestamp":1787875200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100014935","name":"BioCryst Pharmaceuticals Inc","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100014935","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disease of heterotopic ossification (HO) caused by mutations in the activin receptor-like kinase-2 (ALK2) protein, a BMP type I receptor of the TGF-\u03b2 superfamily. These mutations in the ALK2 receptor alter receptor function, causing activin A, a protein that normally inhibits ALK2 signaling, to aberrantly trigger suppressor of mothers against decapentaplegic 1\/5\/8 (SMAD1\/5\/8) signaling, thereby activating the chondroosteogenic pathway and leading to HO. Here we report the initial characterization of BCX9250, an orally available small-molecule inhibitor of ALK2 developed by BioCryst with the potential to treat FOP. Inhibition of ALK2-mediated signaling by BCX9250 was assessed using biochemical binding assays and in vitro activity assays with the mouse myoblast C2C12 cell line. The impact of BCX9250 on HO was investigated using 2 mouse models and an HO recurrence mouse model. BCX9250 has potent inhibitory activity against wild-type ALK2 protein and mutant ALK2 protein associated with FOP. In the ALK2R206H-expressing C2C12 cells, BCX9250 potently inhibited activin A-induced SMAD1 phosphorylation. In the selectivity assays, BCX9250 also potently inhibited several other protein kinases. Oral delivery of BCX9250 significantly reduced HO in 2 mouse models, including the Acvr1R206H knock-in mouse FOP model. BCX9250 also reduced the recurrence of HO after surgical removal of HO, suggesting that ALK2 inhibitors may be beneficial as prophylactic treatments following surgical excision of HO. These results suggest that BCX9250 may be useful for the treatment of FOP.<\/jats:p>","DOI":"10.1093\/jbmrpl\/ziag145","type":"journal-article","created":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T17:21:56Z","timestamp":1787937716000},"source":"Crossref","is-referenced-by-count":0,"title":["BCX9250 is a potent small-molecule inhibitor of Activin A Receptor Type 1 (ACVR1\/ALK2) for fibrodysplasia ossificans progressiva"],"prefix":"10.1093","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2340-0739","authenticated-orcid":false,"given":"Haitao","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Medicine, Section of Geriatric Medicine & Gerontology, Mayo Clinic , Rochester, MN 55905 ,","place":["United States"]},{"name":"Department of Physiology and Biomedical Engineering, Mayo Clinic , Rochester, MN 55905 ,","place":["United 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Endocrinology and Hospital Internal Medicine, Department of Physiology and Biomedical Engineering, Mayo Clinic , Rochester, MN 55905 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-6289-847X","authenticated-orcid":false,"given":"Xiaogang","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Biology, BioCryst Pharmaceuticals Inc., Discovery Center of Excellence , Birmingham, AL 35244 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-0457-1931","authenticated-orcid":false,"given":"Cynthia Davis","family":"Parker","sequence":"additional","affiliation":[{"name":"Department of Biology, BioCryst Pharmaceuticals Inc., Discovery Center of Excellence , Birmingham, AL 35244 ,","place":["United 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Discovery Center of Excellence , Birmingham, AL 35244 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4376-150X","authenticated-orcid":false,"given":"Kevin J","family":"Polach","sequence":"additional","affiliation":[{"name":"Department of Biology, BioCryst Pharmaceuticals Inc., Discovery Center of Excellence , Birmingham, AL 35244 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3694-6506","authenticated-orcid":false,"given":"Pravin L","family":"Kotian","sequence":"additional","affiliation":[{"name":"Department of Biology, BioCryst Pharmaceuticals Inc., Discovery Center of Excellence , Birmingham, AL 35244 ,","place":["United States"]},{"name":"Department of Discovery Chemistry, BioCryst Pharmaceuticals Inc., Discovery Center of Excellence , Birmingham, AL 35244 ,","place":["United 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