{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T22:06:24Z","timestamp":1791324384757,"version":"4.3.1"},"reference-count":39,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"749","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2024,5,29]]},"abstract":"<jats:p>\n            Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease driven by gain-of-function variants in activin receptor\u2013like kinase 2 (ALK2), the most common variant being ALK2\n            <jats:sup>R206H<\/jats:sup>\n            . In FOP, ALK2 variants display increased and dysregulated signaling through the bone morphogenetic protein (BMP) pathway resulting in progressive and permanent replacement of skeletal muscle and connective tissues with heterotopic bone, ultimately leading to severe debilitation and premature death. Here, we describe the discovery of BLU-782 (IPN60130), a small-molecule ALK2\n            <jats:sup>R206H<\/jats:sup>\n            inhibitor developed for the treatment of FOP. A small-molecule library was screened in a biochemical ALK2 binding assay to identify potent ALK2 binding compounds. Iterative rounds of structure-guided drug design were used to optimize compounds for ALK2\n            <jats:sup>R206H<\/jats:sup>\n            binding, ALK2 selectivity, and other desirable pharmacokinetic properties. BLU-782 preferentially bound to ALK2\n            <jats:sup>R206H<\/jats:sup>\n            with high affinity, inhibiting signaling from ALK2\n            <jats:sup>R206H<\/jats:sup>\n            and other rare FOP variants in cells in vitro without affecting signaling of closely related homologs ALK1, ALK3, and ALK6. In vivo efficacy of BLU-782 was demonstrated using a conditional knock-in ALK2\n            <jats:sup>R206H<\/jats:sup>\n            mouse model, where prophylactic oral dosing reduced edema and prevented cartilage and heterotopic ossification (HO) in both muscle and bone injury models. BLU-782 treatment preserved the normal muscle-healing response in ALK2\n            <jats:sup>R206H<\/jats:sup>\n            mice. Delayed dosing revealed a short 2-day window after injury when BLU-782 treatment prevented HO in ALK2\n            <jats:sup>R206H<\/jats:sup>\n            mice, but dosing delays of 4 days or longer abrogated HO prevention. Together, these data suggest that BLU-782 may be a candidate for prevention of HO in FOP.\n          <\/jats:p>","DOI":"10.1126\/scitranslmed.abp8334","type":"journal-article","created":{"date-parts":[[2024,5,29]],"date-time":"2024-05-29T17:59:08Z","timestamp":1717005548000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":23,"title":["An ALK2 inhibitor, BLU-782, prevents heterotopic ossification in a mouse model of fibrodysplasia ossificans progressiva"],"prefix":"10.1126","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4425-7871","authenticated-orcid":true,"given":"Alison J.","family":"Davis","sequence":"first","affiliation":[{"name":"Blueprint Medicines Corporation, Cambridge, MA 02139, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3514-4189","authenticated-orcid":true,"given":"Natasja","family":"Brooijmans","sequence":"additional","affiliation":[{"name":"Blueprint Medicines Corporation, Cambridge, MA 02139, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason D.","family":"Brubaker","sequence":"additional","affiliation":[{"name":"Blueprint Medicines Corporation, Cambridge, MA 02139, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7318-060X","authenticated-orcid":true,"given":"Faith","family":"Stevison","sequence":"additional","affiliation":[{"name":"Blueprint Medicines Corporation, Cambridge, MA 02139, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4715-638X","authenticated-orcid":true,"given":"Timothy P.","family":"LaBranche","sequence":"additional","affiliation":[{"name":"Blueprint Medicines Corporation, Cambridge, MA 02139, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-2271-6348","authenticated-orcid":true,"given":"Faris","family":"Albayya","sequence":"additional","affiliation":[{"name":"Blueprint Medicines Corporation, Cambridge, MA 02139, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3009-0858","authenticated-orcid":true,"given":"Paul","family":"Fleming","sequence":"additional","affiliation":[{"name":"Blueprint Medicines Corporation, Cambridge, MA 02139, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian L.","family":"Hodous","sequence":"additional","affiliation":[{"name":"Blueprint Medicines Corporation, Cambridge, MA 02139, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7739-2343","authenticated-orcid":true,"given":"Joseph L.","family":"Kim","sequence":"additional","affiliation":[{"name":"Blueprint Medicines Corporation, Cambridge, MA 02139, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean","family":"Kim","sequence":"additional","affiliation":[{"name":"Blueprint Medicines Corporation, Cambridge, MA 02139, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riadh","family":"Lobbardi","sequence":"additional","affiliation":[{"name":"Blueprint Medicines Corporation, Cambridge, MA 02139, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-7284-833X","authenticated-orcid":true,"given":"Michael","family":"Palmer","sequence":"additional","affiliation":[{"name":"Blueprint Medicines Corporation, Cambridge, MA 02139, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael P.","family":"Sheets","sequence":"additional","affiliation":[{"name":"Blueprint Medicines Corporation, Cambridge, MA 02139, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-0965-5009","authenticated-orcid":true,"given":"John","family":"Vassiliadis","sequence":"additional","affiliation":[{"name":"Blueprint Medicines Corporation, Cambridge, MA 02139, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruduan","family":"Wang","sequence":"additional","affiliation":[{"name":"Blueprint Medicines Corporation, Cambridge, MA 02139, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brett D.","family":"Williams","sequence":"additional","affiliation":[{"name":"Blueprint Medicines Corporation, Cambridge, MA 02139, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-8468-0284","authenticated-orcid":true,"given":"Douglas","family":"Wilson","sequence":"additional","affiliation":[{"name":"Blueprint Medicines Corporation, Cambridge, MA 02139, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lan","family":"Xu","sequence":"additional","affiliation":[{"name":"Blueprint Medicines Corporation, Cambridge, MA 02139, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4422-9766","authenticated-orcid":true,"given":"Xing Julia","family":"Zhu","sequence":"additional","affiliation":[{"name":"Blueprint Medicines Corporation, Cambridge, MA 02139, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith","family":"Bouchard","sequence":"additional","affiliation":[{"name":"Alexion Pharmaceuticals, Boston, MA 02210, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3898-6632","authenticated-orcid":true,"given":"Jeffrey W.","family":"Hunter","sequence":"additional","affiliation":[{"name":"Alexion Pharmaceuticals, Boston, MA 02210, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-4728-0927","authenticated-orcid":true,"given":"Chris","family":"Graul","sequence":"additional","affiliation":[{"name":"Invicro, Boston, MA 02210, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-6848-0817","authenticated-orcid":true,"given":"Elliot","family":"Greenblatt","sequence":"additional","affiliation":[{"name":"Invicro, Boston, MA 02210, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amira","family":"Hussein","sequence":"additional","affiliation":[{"name":"Invicro, Boston, MA 02210, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1148-0674","authenticated-orcid":true,"given":"Morgan","family":"Lyon","sequence":"additional","affiliation":[{"name":"Invicro, Boston, MA 02210, 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USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivek","family":"Kadambi","sequence":"additional","affiliation":[{"name":"Blueprint Medicines Corporation, Cambridge, MA 02139, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Lengauer","sequence":"additional","affiliation":[{"name":"Blueprint Medicines Corporation, Cambridge, MA 02139, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew P.","family":"Garner","sequence":"additional","affiliation":[{"name":"Blueprint Medicines Corporation, Cambridge, MA 02139, 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J.","year":"2013","unstructured":"R. J. Pignolo, E. M. Shore, F. S. Kaplan, Fibrodysplasia ossificans progressiva: Diagnosis, management, and therapeutic horizons. Pediatr. Endocrinol. Rev. 10, 437\u2013448 (2013).","journal-title":"Pediatr. Endocrinol. Rev."},{"key":"e_1_3_2_7_2","first-page":"325","article-title":"Clinical aspects and current therapeutic approaches for FOP","volume":"8","author":"Kitoh H.","year":"2020","unstructured":"H. Kitoh, Clinical aspects and current therapeutic approaches for FOP. Biomedicine 8, 325 (2020).","journal-title":"Biomedicine"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1385\/BMM:3:3-4:213"},{"key":"e_1_3_2_9_2","first-page":"1","article-title":"The medical management of fibrodysplasia ossificans progressiva: Current treatment considerations","volume":"1","author":"Kaplan F. S.","year":"2019","unstructured":"F. S. Kaplan, M. Al Mukaddam, G. Baujat, M. Brown, A. Cali, T.-J. Cho, C. Crow, C. De Cunto, P. Delai, R. Diecidue, M. Di Rocco, E. M. W. Eekhoff, C. Friedman, Z. Grunwald, N. Haga, E. Hsiao, R. Keen, J. Kitterman, C. Levy, R. Morhart, C. Netelenbos, C. Scott, E. M. Shore, M. Zasloff, K. Zhang, R. J. Pignolo, The medical management of fibrodysplasia ossificans progressiva: Current treatment considerations. Proc. Intl. Clin. Council FOP 1, 1\u2013111 (2019).","journal-title":"Proc. Intl. Clin. Council FOP"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1075762"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20868"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1783"},{"key":"e_1_3_2_13_2","first-page":"3462","article-title":"The fibrodysplasia ossificans progressiva R206H ACVR1 mutation activates BMP-independent chondrogenesis and zebrafish embryo ventralization","volume":"119","author":"Shen Q.","year":"2009","unstructured":"Q. Shen, S. C. Little, M. Xu, J. Haupt, C. Ast, T. Katagiri, S. Mundlos, P. Seemann, F. S. 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Di Rocco E. Forleo-Neto R. Pignolo R. Keen P. Orcel T. Funck-Brentano C. Roux S. Kolta A. Madeo J. S. Bubbear J. Tabarkiewicz M. Szczepanek J. Bachiller-Corral A. M. Cheung K. M. Dahir E. Botman P. G. Raijmakers M. Al Mukaddam L. Tile C. Portal-Celhay N. Sarkar P. Hou B. Musser A. Boyapati K. Mohammadi S. Mellis A. J. Rankin A. N. Economides D. G. Trotter G. Herman S. J. O\u2019Meara R. DelGizzi D. M. Weinreich G. D. Yancopolous E. M. W. Eekhoff F. S. Kaplan Garetosmab an inhibitor of activin A reduces heterotopic ossification and flare-ups in adults with fibrodysplasia ossificans progressiva: A randomized double-blind placebo-controlled phase 2 trial. medRxiv 01.11.23284254 (2023).","DOI":"10.1101\/2023.01.11.23284254"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.2820"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.40814"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1021\/acsomega.1c02983"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1248\/cpb.c19-00882"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.str.2008.12.023"}],"container-title":["Science Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/scitranslmed.abp8334","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,29]],"date-time":"2024-05-29T17:59:32Z","timestamp":1717005572000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.abp8334"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,29]]},"references-count":39,"journal-issue":{"issue":"749","published-print":{"date-parts":[[2024,5,29]]}},"alternative-id":["10.1126\/scitranslmed.abp8334"],"URL":"https:\/\/doi.org\/10.1126\/scitranslmed.abp8334","relation":{},"ISSN":["1946-6234","1946-6242"],"issn-type":[{"value":"1946-6234","type":"print"},{"value":"1946-6242","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,5,29]]},"assertion":[{"value":"2022-07-01","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-05-07","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-05-29","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eabp8334"}}