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dc.contributor.author | Sánchez-Duffhues, Gonzalo | |
dc.contributor.author | Williams, Eleanor | |
dc.contributor.author | Benderitter, Pascal | |
dc.contributor.author | Orlova, Valeria | |
dc.contributor.author | van Wijhe, Michiel | |
dc.contributor.author | Garcia de Vinuesa, Amaya | |
dc.contributor.author | Kerr, Georgina | |
dc.contributor.author | Caradec, Josselin | |
dc.contributor.author | Lodder, Kirsten | |
dc.contributor.author | de Boer, Hetty C | |
dc.contributor.author | Goumans, Marie-José | |
dc.contributor.author | Eekhoff, Elisabeth M W | |
dc.contributor.author | Morales-Piga, Antonio | |
dc.contributor.author | Bachiller-Corral, Javier | |
dc.contributor.author | Koolwijk, Pieter | |
dc.contributor.author | Bullock, Alex N | |
dc.contributor.author | Hoflack, Jan | |
dc.contributor.author | Ten Dijke, Peter | |
dc.date.accessioned | 2021-06-18T15:07:11Z | |
dc.date.available | 2021-06-18T15:07:11Z | |
dc.date.issued | 2019-11 | |
dc.identifier.citation | JBMR Plus. 2019 Oct 7;3(11):e10230. | es_ES |
dc.identifier.uri | http://hdl.handle.net/20.500.12105/13165 | |
dc.description.abstract | Fibrodysplasia 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.sponsorship | GSD 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.iso | eng | es_ES |
dc.publisher | Wiley | es_ES |
dc.type.hasVersion | VoR | es_ES |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | * |
dc.subject | Bone Morphogenetic Protein | es_ES |
dc.subject | Endothelial | es_ES |
dc.subject | Endothelial‐To‐Mesenchymal Transition | es_ES |
dc.subject | Fibrodysplasia Ossificans Progressiva | es_ES |
dc.subject | Osteoblast; Tgf‐Β | es_ES |
dc.title | Development of Macrocycle Kinase Inhibitors for ALK2 Using Fibrodysplasia Ossificans Progressiva-Derived Endothelial Cells | es_ES |
dc.type | journal article | es_ES |
dc.rights.license | Atribución 4.0 Internacional | * |
dc.identifier.pubmedID | 31768489 | es_ES |
dc.format.volume | 3 | es_ES |
dc.format.number | 11 | es_ES |
dc.format.page | e10230 | es_ES |
dc.identifier.doi | 10.1002/jbm4.10230 | es_ES |
dc.contributor.funder | Telethon Foundation | |
dc.contributor.funder | AO Foundation | |
dc.contributor.funder | Cancer Genomics Centre (Países Bajos) | |
dc.description.peerreviewed | Sí | es_ES |
dc.identifier.e-issn | 2473-4039 | es_ES |
dc.relation.publisherversion | https://doi.org/10.1002/jbm4.10230 | es_ES |
dc.identifier.journal | JBMR Plus | es_ES |
dc.repisalud.centro | ISCIII::Instituto de Investigación de Enfermedades Raras | es_ES |
dc.repisalud.institucion | ISCIII | es_ES |
dc.rights.accessRights | open access | es_ES |