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Bone. 2017 Dec;105:57-66. doi: 10.1016/j.bone.2017.08.016. Epub 2017 Aug 18.

ARQ 087 inhibits FGFR signaling and rescues aberrant cell proliferation and differentiation in experimental models of craniosynostoses and chondrodysplasias caused by activating mutations in FGFR1, FGFR2 and FGFR3.

Author information

1
Institute of Experimental Biology, Faculty of Sciences, Masaryk University, 62500 Brno, Czech Republic; Department of Biology, Faculty of Medicine, Masaryk University, 62500 Brno, Czech Republic.
2
Department of Biology, Faculty of Medicine, Masaryk University, 62500 Brno, Czech Republic.
3
Institute of Animal Physiology and Genetics, Czech Academy of Sciences, 60200 Brno, Czech Republic.
4
Institute of Experimental Biology, Faculty of Sciences, Masaryk University, 62500 Brno, Czech Republic; Institute of Animal Physiology and Genetics, Czech Academy of Sciences, 60200 Brno, Czech Republic.
5
Department of Biology, Faculty of Medicine, Masaryk University, 62500 Brno, Czech Republic; International Clinical Research Center, St. Anne's University Hospital, 65691 Brno, Czech Republic.
6
ArQule, Burlington, MA 01803, USA.
7
University of Michigan School of Dentistry, University of Michigan, Ann Arbor, MI 48109, USA.
8
Institute of Experimental Biology, Faculty of Sciences, Masaryk University, 62500 Brno, Czech Republic; Institute of Animal Physiology and Genetics, Czech Academy of Sciences, 60200 Brno, Czech Republic. Electronic address: buchtova@iach.cz.
9
Department of Biology, Faculty of Medicine, Masaryk University, 62500 Brno, Czech Republic; International Clinical Research Center, St. Anne's University Hospital, 65691 Brno, Czech Republic. Electronic address: krejcip@med.muni.cz.

Abstract

Tyrosine kinase inhibitors are being developed for therapy of malignancies caused by oncogenic FGFR signaling but little is known about their effect in congenital chondrodysplasias or craniosynostoses that associate with activating FGFR mutations. Here, we investigated the effects of novel FGFR inhibitor, ARQ 087, in experimental models of aberrant FGFR3 signaling in cartilage. In cultured chondrocytes, ARQ 087 efficiently rescued all major effects of pathological FGFR3 activation, i.e. inhibition of chondrocyte proliferation, loss of extracellular matrix and induction of premature senescence. In ex vivo tibia organ cultures, ARQ 087 restored normal growth plate architecture and eliminated the suppressing FGFR3 effect on chondrocyte hypertrophic differentiation, suggesting that it targets the FGFR3 pathway specifically, i.e. without interference with other pro-growth pathways. Moreover, ARQ 087 inhibited activity of FGFR1 and FGFR2 mutants associated with Pfeiffer, Apert and Beare-Stevenson craniosynostoses, and rescued FGFR-driven excessive osteogenic differentiation in mouse mesenchymal micromass cultures or in ex vivo calvarial organ cultures. Our data warrant further development of ARQ 087 for clinical use in skeletal disorders caused by activating FGFR mutations.

KEYWORDS:

ARQ 087; Achondroplasia; Craniosynostosis; FGFR; Fibroblast growth factor receptor; Inhibitor; Skeletal dysplasia

PMID:
28826843
DOI:
10.1016/j.bone.2017.08.016
[Indexed for MEDLINE]

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