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Mohedas, Agustin

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Mohedas

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Agustin

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Mohedas, Agustin
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    Two tissue-resident progenitor lineages drive distinct phenotypes of heterotopic ossification
    (American Association for the Advancement of Science (AAAS), 2016) Dey, D.; Bagarova, J.; Hatsell, S. J.; Armstrong, K. A.; Huang, L.; Ermann, J.; Vonner, A. J.; Shen, Y.; Mohedas, Agustin; Lee, A.; Eekhoff, E. M. W.; van Schie, A.; Demay, Marie; Keller, C.; Wagers, Amy; Economides, A. N.; Yu, P. B.
    Fibrodysplasia ossificans progressiva (FOP), a congenital HO syndrome caused by gain-of-function mutations of bone morphogenetic protein (BMP) type I receptor ACVR1, manifests with progressive ossification of diverse tissues including skeletal muscles, tendons, ligaments, fascia and joints. HO can occur in discrete flares, often triggered by injury or inflammation, or may progress incrementally without identified triggers. Mice harboring an Acvr1R206H knock-in allele recapitulated the phenotypic spectrum of FOP, including injuryresponsive intramuscular HO, and spontaneous articular, tendon and ligament ossification. HO in these distinct sites was formed by two anatomically distinct progenitor lineages: A muscle-resident interstitial Mx1+Sca1+LinPDGFRα+ population which was sufficient to facilitate intramuscular, injury-dependent endochondral HO, and an Scx+Sca1+Lin-PDGFRα+tendon-derived progenitor which was sufficient to initiate ligament and articular endochondral HO without injury. The cell-autonomous effects of Acvr1R206H in both of these lineages promoted heterotopic chondrogenesis, and conferred to cells abnormal gain of BMP signaling and endochondral differentiation in response to Activin A. Both injury-dependent intramuscular and spontaneous ligament HO in Acvr1R206H knock-in mice were effectively controlled by the selective ACVR1 inhibitor LDN-212854. The diverse spatiotemporal manifestations of HO in FOP are rooted in cell-autonomous effects of dysregulated ACVR1 signaling in multiple non-overlapping tissue-resident progenitors, with direct implications for therapies designed to modify their recruitment or plasticity.
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    A New Class of Small Molecule Inhibitor of BMP Signaling
    (Public Library of Science, 2013) Sanvitale, Caroline E.; Kerr, Georgina; Chaikuad, Apirat; Ramel, Marie-Christine; Mohedas, Agustin; Reichert, Sabine; Wang, You; Triffitt, James T.; Cuny, Gregory D.; Yu, Paul; Hill, Caroline S.; Bullock, Alex N.
    Growth factor signaling pathways are tightly regulated by phosphorylation and include many important kinase targets of interest for drug discovery. Small molecule inhibitors of the bone morphogenetic protein (BMP) receptor kinase ALK2 (ACVR1) are needed urgently to treat the progressively debilitating musculoskeletal disease fibrodysplasia ossificans progressiva (FOP). Dorsomorphin analogues, first identified in zebrafish, remain the only BMP inhibitor chemotype reported to date. By screening an assay panel of 250 recombinant human kinases we identified a highly selective 2-aminopyridine-based inhibitor K02288 with in vitro activity against ALK2 at low nanomolar concentrations similar to the current lead compound LDN-193189. K02288 specifically inhibited the BMP-induced Smad pathway without affecting TGF-β signaling and induced dorsalization of zebrafish embryos. Comparison of the crystal structures of ALK2 with K02288 and LDN-193189 revealed additional contacts in the K02288 complex affording improved shape complementarity and identified the exposed phenol group for further optimization of pharmacokinetics. The discovery of a new chemical series provides an independent pharmacological tool to investigate BMP signaling and offers multiple opportunities for pre-clinical development.