Journal article
Development of macrocycle kinase inhibitors for ALK2 using Fibrodysplasia ossificans progressiva‐derived endothelial cells
- Abstract:
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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 discover 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.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, pdf, 19.0MB, Terms of use)
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- Publisher copy:
- 10.1002/jbm4.10230
Authors
- Publisher:
- Wiley
- Journal:
- JBMR Plus More from this journal
- Volume:
- 3
- Issue:
- 11
- Pages:
- e10230
- Publication date:
- 2019-10-07
- Acceptance date:
- 2019-08-06
- DOI:
- EISSN:
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2473-4039
- Keywords:
- Pubs id:
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pubs:1039497
- UUID:
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uuid:3f89f36a-ce63-4508-940b-02ce522b0264
- Local pid:
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pubs:1039497
- Source identifiers:
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1039497
- Deposit date:
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2019-08-07
Terms of use
- Copyright holder:
- Sánchez‐Duffhues et al
- Copyright date:
- 2019
- Notes:
- © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- Licence:
- CC Attribution (CC BY)
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