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Beschreibung

A cell-permeable, bioavailable, conformationally restricted form of CCG-1423 (Cat. No. 555558) that exhibits enhanced potency (IC50 = 4.2 µ,M vs 16.6 µ,M for PC-3 cell migration), but reduced off-target toxicity (IC50 >100 µ,M in PC3 cells). Selectively represses sclerodermal fibroblasts proliferation without affecting normal cells (~30 µ,M). Shown to be more effective in reducing MRTF/SRF-regulated gene transcriptional signaling than Y-27632 (Cat. No. 688000). Suppresses Rho/MRTF/SRF-regulated fibrotic gene expression in primary dermal fibroblasts derived from systemic sclerosis patients in a dose-dependent manner and reverses myofibroblast phenotype in TGFbeta-stimulated normal dermal fibroblasts. Blocks MRTF nuclear localization by interfering with the microtubule associated monooxygenase, calponin and LIM domain containing 2 (MICAL-2), mediated regulation of intranuclear actin polymerization. Although exhibits a short in-vivo half-life (~25 min), at higher dosage effectively prevents bleomycin-induced fibrosis in C57BL/6J mice (100 mg/kg, i.p., b.i.d.).Please note that the molecular weight for this compound is batch-specific due to variable water content., A cell-permeable nipecotic bis(amide), chemically modified from CCG-1423 (Cat. No. 555558) for reduced toxicity (non-toxic up to 100 µ,M in PC-3 cultures and 100 mg/kg/d in mice via i.p.), that effectively downregulates SRF/MLK1 (MRTF-A) target genes mRNA level in primary dermal fibroblast cultures from SSc (systemic sclerosis) patients (IC50 <=30 µ,M post 24 h incubation) as well as in LPA-stimulated NIH 3T3 fibroblasts (IC50 = 1 - 3 µ,M, drug added 23 h prior to 1 h 10 µ,M LPA stimulation). Likewise, 3-day 10 µ,M CCG-203971 treatment is shown to reduce cellular alpha-SMA (alpha smooth muscle actin) protein and proliferation of SSc dermal fibroblasts to the same level as seen in dermal fibroblasts from healthy donors as well as to prevent 10 ng/mL TGFbeta-induced alpha-SMA upregulation in normal dermal fibroblasts. When administered via intraperitoneal injection (100 mg/50 µ,L DMSO/kg/12 h), CCG-203971 is reported to be efficacious in preventing bleomycin-(100 µ,g/µ,L/1 cm2 skin/animal/day s.c.) induced skin fibrosis in mice (skin thickness = 1.9- vs. 3.5-fold of control, with or without drug treatment at the end of 2-wk induction period) in vivo., A cell-permeable, restricted form of CCG-1423 with enhanced potency (IC₅,₀, = 4.2 µ,M vs 16.6 µ,M for PC-3 cell migration), but reduced off-target toxicity.