4-(4-chloro-2-methylphenoxy)-n-hydroxybutanamide and Idiopathic-Pulmonary-Fibrosis

Regenerative capacity in vital organs is limited by fibrosis propensity. Idiopathic pulmonary fibrosis (IPF), a progressive lung disease linked with aging, is a classic example. In this study, we show that in flow cytometry, immunoblots (IB) and in lung sections, FLIP levels can be regulated, in vivo and in vitro, through SIRT1 activity inhibition by CMH (4-(4-Chloro-2-methylphenoxy)-N-hydroxybutanamide), a small molecule that, as we determined here by structural biology calculations, docked into its nonhistone substrate Ku70-binding site. Ku70 immunoprecipitations and immunoblots confirmed our theory that Ku70-deacetylation, Ku70/FLIP complex, myofibroblast resistance to apoptosis, cell survival, and lung fibrosis in bleomycin-treated mice, are reduced and regulated by CMH. Thus, small molecules associated with SIRT1-mediated regulation of Ku70 deacetylation, affecting FLIP stabilization in fibrotic-lung myofibroblasts, may be a useful strategy, enabling tissue regeneration.

Topics: Acetylation; Animals; Binding Sites; CASP8 and FADD-Like Apoptosis Regulating Protein; Cell Line; Cell Survival; Disease Models, Animal; Fibroblasts; Gene Expression Regulation; Humans; Hydroxamic Acids; Idiopathic Pulmonary Fibrosis; Ku Autoantigen; Lung; Male; Mice; Mice, Inbred C57BL; Models, Molecular; Molecular Docking Simulation; Protein Conformation; Protein Stability; Sirtuin 1