Open AccessDevelopment of Macrocycle Kinase Inhibitors for ALK2 Using Fibrodysplasia Ossificans Progressiva‐Derived Endothelial Cells
Author(s) -
SánchezDuffhues Gonzalo,
Williams Eleanor,
Benderitter Pascal,
Orlova Valeria,
Wijhe Michiel,
Garcia de Vinuesa Amaya,
Kerr Georgina,
Caradec Josselin,
Lodder Kirsten,
Boer Hetty C.,
Goumans MarieJosé,
Eekhoff Elisabeth M W,
MoralesPiga Antonio,
BachillerCorral Javier,
Koolwijk Pieter,
Bullock Alex N.,
Hoflack Jan,
Dijke Peter
Publication year - 2019
Publication title -
jbmr plus
Language(s) - English
Resource type - Journals
ISSN - 2473-4039
DOI - 10.1002/jbm4.10230
Subject(s) - fibrodysplasia ossificans progressiva , activin receptor , ossification , mesenchymal stem cell , heterotopic ossification , cancer research , microbiology and biotechnology , bone morphogenetic protein , signal transduction , bone morphogenetic protein 2 , bmpr2 , myositis ossificans , medicine , bioinformatics , chemistry , biology , pathology , biochemistry , anatomy , gene , in vitro
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.