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Tibial pseudarthrosis often features deficient bone formation, excessive bone resorption, and extensive pathological fibrosis, particularly in individuals with Neurofibromatosis type I (NF1). Itwas hypothesized that overactive NF1-Ras-JNK signalling may underlie the pathological fibrosis, and that this could be treated via a JNK antagonist. CC-930, a small molecule JNK inhibitor, was trialed in closed fractures in wild type mice CC-930 (25 mg/kg/twice daily)was dosed throughout fracture healing (D2-21) and during the latter stages of repair (D11-21). All fractures healed by D21, regardless of treatment, with some of the CC-930 (D11-21) treatment group showing early bridging. CC-930 (D11-21) was tested in an Nf1-null fracture model where Nf1 was inactivated by Ad-Cre virus injection in Nf1flox/flox mice; these mice also possessed a Cre-responsive tdTomato transgene. CC-930 resulted in a significant decrease in non-unions (93% vehicle vs. 64% CC-930, p < 0.01). Local treatment with the bone anabolic rhBMP-2 (10mg) increased union and callus bone volume, but also increased the fibrotic tissue at the fracture site. Fractures treated with a combination of rhBMP-2 (10mg) and CC-930 were all partially or fully bridged by D21 (p < 0.01 vs. vehicle) and there was a significant decrease in fibrosis vs. rhBMP-2 alone (p < 0.01). In untreated Nf1- null fractures, the tdTomato transgene was expressed in fibrous tissue at the fracture site, but not in the newly forming bone. These data suggest that JNK inhibition may be an effective therapeutic approach for reducing pathological fibrosis in NF1 tibial pseudarthrosis, however other adjunctive strategies may be required to augment bone formation. [ABSTRACT FROM AUTHOR]

publisher‐imprint‐name Springer volume‐issue‐count 1 issue‐article‐count 0 issue‐toc‐levels 0 issue‐pricelist‐year 2016 issue‐copyright‐holder The Author(s) issue‐copyright‐year 2016 article‐contains‐esm Yes article‐numbering‐style Unnumbered article‐registration‐date‐year 2016 article‐registration‐date‐month 8 article‐registration‐date‐day 10 article‐toc‐levels 0 toc‐levels 0 volume‐type Regular journal‐product ArchiveJournal numbering‐style Unnumbered article‐grants‐type OpenChoice metadata‐grant OpenAccess abstract‐grant OpenAccess bodypdf‐grant OpenAccess bodyhtml‐grant OpenAccess bibliography‐grant OpenAccess esm‐grant OpenAccess online‐first false pdf‐file‐reference BodyRef/PDF/40169_2016_Article_117.pdf pdf‐type Typeset target‐type OnlinePDF issue‐type Regular article‐type OriginalPaper journal‐subject‐primary Medicine & Public Health journal‐subject‐secondary Medicine/Public Health, general journal‐subject‐collection Medicine open‐access true --> Background: Lung remodeling and pulmonary fibrosis are serious, life‐threatening conditions resulting from diseases such as chronic severe asthma and idiopathic pulmonary fibrosis (IPF). Preclinical evidence suggests that JNK enzyme function is required for key steps in the pulmonary fibrotic process. However, a selective JNK inhibitor has not been investigated in translational models of lung fibrosis with clinically relevant biomarkers, or in IPF patients. Methods: The JNK inhibitor CC‐930 was evaluated in the house dust mite‐induced fibrotic airway mouse model, in a phase I healthy volunteer pharmacodynamic study, and subsequently in a phase II multicenter study of mild/moderate IPF (n = 28), with a 4‐week, placebo‐controlled, double‐blind, sequential ascending‐dose period (50 mg QD, 100 mg QD, 100 mg BID) and a 52‐week open‐label treatment‐extension period. Results: In the preclinical model, CC‐930 attenuated collagen 1A1 gene expression, peribronchiolar collagen deposition, airway mucin MUC5B expression in club cells, and MMP‐7 expression in lung, bronchoalveolar lavage fluid, and serum. In the phase I study, CC‐930 reduced c‐Jun phosphorylation induced by UV radiation in skin. In the phase II IPF study, there was a CC‐930 dose‐dependent trend in reduction of MMP‐7 and SP‐D plasma protein levels. The most commonly reported adverse events were increased ALT, increased AST, and upper respiratory tract infection (six subjects each, 21.4 %). A total of 13 subjects (46.4 %) experienced adverse events that led to discontinuation of study drug. Nine out of 28 subjects experienced progressive disease in this study. The mean FVC (% predicted) declined after 26–32 weeks at doses of 100 mg QD and 100 mg BID. Changes in MMP‐7, SP‐D, and tenascin‐C significantly correlated with change in FVC (% predicted). Conclusions: These results illustrate JNK enzymatic activity involvement during pulmonary fibrosis, and support systemic biomarker use for tracking disease progression and the potential clinical benefit of this novel intervention in IPF. Trial registration ClinicalTrials.gov NCT01203943 [ABSTRACT FROM AUTHOR]

Abstract: In this Letter we describe the discovery of potent, selective, and orally active aminopurine JNK inhibitors. Improving the physico-chemical properties as well as increasing the potency and selectivity of a subseries with rat plasma exposure, led to the identification of four structurally diverse inhibitors. Differentiation based on PK profiles in multiple species as well as activity in a chronic efficacy model led to the identification of 1 (CC-930) as a development candidate, which is currently in Phase II clinical trial for IPF. [Copyright &y& Elsevier]