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dc.contributor.authorSánchez-Duffhues, Gonzalo
dc.contributor.authorWilliams, Eleanor
dc.contributor.authorBenderitter, Pascal
dc.contributor.authorOrlova, Valeria
dc.contributor.authorvan Wijhe, Michiel
dc.contributor.authorGarcia de Vinuesa, Amaya
dc.contributor.authorKerr, Georgina
dc.contributor.authorCaradec, Josselin
dc.contributor.authorLodder, Kirsten
dc.contributor.authorde Boer, Hetty C
dc.contributor.authorGoumans, Marie-José
dc.contributor.authorEekhoff, Elisabeth M W
dc.contributor.authorMorales-Piga, Antonio 
dc.contributor.authorBachiller-Corral, Javier
dc.contributor.authorKoolwijk, Pieter
dc.contributor.authorBullock, Alex N
dc.contributor.authorHoflack, Jan
dc.contributor.authorTen Dijke, Peter
dc.date.accessioned2021-06-18T15:07:11Z
dc.date.available2021-06-18T15:07:11Z
dc.date.issued2019-11
dc.identifier.citationJBMR Plus. 2019 Oct 7;3(11):e10230.es_ES
dc.identifier.urihttp://hdl.handle.net/20.500.12105/13165
dc.description.abstractFibrodysplasia ossificans progressiva (FOP) is an extremely rare congenital form of heterotopic ossification (HO), caused by heterozygous mutations in the activin A type I receptor (ACVR1), that encodes the bone morphogenetic protein (BMP) type I receptor ALK2. These mutations enable ALK2 to induce downstream signaling in response to activins, thereby turning them into bone-inducing agents. To date, there is no cure for FOP. The further development of FOP patient-derived models may contribute to the discovery of novel biomarkers and therapeutic approaches. Nevertheless, this has traditionally been a challenge, as biopsy sampling often triggers HO. We have characterized peripheral blood-derived endothelial colony-forming cells (ECFCs) from three independent FOP donors as a new model for FOP. FOP ECFCs are prone to undergo endothelial-to-mesenchymal transition and exhibit increased ALK2 downstream signaling and subsequent osteogenic differentiation upon stimulation with activin A. Moreover, we have identified a new class of small molecule macrocycles with potential activity against ALK2 kinase. Finally, using FOP ECFCs, we have selected OD36 and OD52 as potent inhibitors with excellent kinase selectivity profiles that potently antagonize mutant ALK2 signaling and osteogenic differentiation. We expect that these results will contribute to the development of novel ALK2 clinical candidates for the treatment of FOP. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.es_ES
dc.description.sponsorshipGSD was supported by AFM‐Telethon (#18365, #22379), the Start‐Up grant (S12‐27S) from the AO Foundation and the RECONNECT Consortium (belonging to the Netherlands Cardiovascular Research Initiative: the Dutch Heart Foundation, Dutch Federation of University Medical Centres, the Netherlands Organization for Health Research and Development, and the Royal Netherlands Academy of Sciences. PtD was supported by the Cancer Genomics Centre Netherlands (CGC.nl). We would like to acknowledge Dr. Garcia Castro (ISCIII Madrid, Spain) for making his lab available. We would like to specially acknowledge the collaboration of the Dutch (FOP Stichting Nederland) and Spanish (AEFOP) FOP patients and relatives. We thank Diamond Light Source for beamtime (proposal mx8421), as well as the staff of Beamline I04 for assistance with data collection. The SGC is a registered charity (number 1097737) that receives funds from AbbVie, Bayer Pharma AG, Boehringer Ingelheim, Canada Foundation for Innovation, Eshelman Institute for Innovation, Genome Canada, Innovative Medicines Initiative (EU/EFPIA) [ULTRA‐DD grant no. 115766], Janssen, Merck KGaA Darmstadt Germany, MSD, Novartis Pharma AG, Ontario Ministry of Economic Development and Innovation, Pfizer, São Paulo Research Foundation‐FAPESP, Takeda, and Wellcome [106169/ZZ14/Z]. We would like to acknowledge Emilie Jigorel and Lionel Trottet for technical support.es_ES
dc.language.isoenges_ES
dc.publisherWiley es_ES
dc.type.hasVersionVoRes_ES
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.subjectBone Morphogenetic Proteines_ES
dc.subjectEndotheliales_ES
dc.subjectEndothelial‐To‐Mesenchymal Transitiones_ES
dc.subjectFibrodysplasia Ossificans Progressivaes_ES
dc.subjectOsteoblast; Tgf‐Βes_ES
dc.titleDevelopment of Macrocycle Kinase Inhibitors for ALK2 Using Fibrodysplasia Ossificans Progressiva-Derived Endothelial Cellses_ES
dc.typejournal articlees_ES
dc.rights.licenseAtribución 4.0 Internacional*
dc.identifier.pubmedID31768489es_ES
dc.format.volume3es_ES
dc.format.number11es_ES
dc.format.pagee10230es_ES
dc.identifier.doi10.1002/jbm4.10230es_ES
dc.contributor.funderTelethon Foundation
dc.contributor.funderAO Foundation 
dc.contributor.funderCancer Genomics Centre (Países Bajos)
dc.description.peerreviewedes_ES
dc.identifier.e-issn2473-4039es_ES
dc.relation.publisherversionhttps://doi.org/10.1002/jbm4.10230es_ES
dc.identifier.journalJBMR Pluses_ES
dc.repisalud.centroISCIII::Instituto de Investigación de Enfermedades Rarases_ES
dc.repisalud.institucionISCIIIes_ES
dc.rights.accessRightsopen accesses_ES


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Atribución 4.0 Internacional
Este Item está sujeto a una licencia Creative Commons: Atribución 4.0 Internacional