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Beschreibung

A cell-permeable pyrazinopyrimidinecarboxamide that competes against &beta,-catenin for CBP (CREB-binding protein) binding and selectively prevents CBP- but not p300-, dependent TCF/&beta,-catenin transcriptional regulations both in cultures in vitro (5 to 25 microM) and in mice in vivo (5 mg/kg/day via osmotic pump infusion), while not affecting CBP-dependent transcriptional activities mediated by the AP-1 or CRE complex. Shown to reactivate p300//TCF/&beta,-catenin-mediated neuronal differentiation upon NGF stimulation in PS-1 L286V mutant-expressing PC-12 cultures and be efficacious in alleviating bleomycin- (0,08 units/50 microL/mouse, administered intranasally, Cat. No. 203401) induced pulmonary fibrosis in mice., A cell-permeable pyrazinopyrimidinecarboxamide that competes against &beta,-catenin for CBP (CREB-binding protein) binding (5 to 10 microM for 24 h in SW480 and C2C12 cultures) and selectively prevents CBP- but not p300-, dependent TCF/&beta,-catenin transcriptional regulations both in cultures in vitro (5 to 25 microM in SW480, HCT116, rat RLT-6TN, and primary human IPF lung fibroblasts, 4 to 24 h) and in mice in vivo (5 mg/kg/day via osmotic pump infusion), while not affecting CBP-dependent transcriptional activities mediated by the AP-1 or CRE complex. Selective blockage of CBP/TCF/&beta,-catenin complex formation by ICG-001 is shown to reactivate p300//TCF/&beta,-catenin-mediated neuronal differentiation upon NGF stimulation in PS-1 L286V mutant-expressing PC-12 cultures (cell population with neurite outgrowth = 90% and 17% of wt PS-1 control level, respectively, with or without 10 microM ICG-001) and be efficacious in alleviating bleomycin- (0,08 units/50 microL/mouse, administered intranasally, Cat. No. 203401) induced pulmonary fibrosis in mice (5 mg/kg/day via osmotic pump infusion, 10 d treatment starting 1 d before bleomycin induction or 21 d treatment starting d 21 post bleomycin induction).