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Beschreibung

A cell-permeable benzothiazolylchromenone compound that disrupts Skp2-Skp1 interaction via direct Skp2 affinity binding and selectively prevents Skp2-, but not Fbw7- or beta-TrCP-, Skp1-Cullin-1-F-box (SFC) complex-mediated substrates ubiquitination both in cell-free systems and in cultures, effectively preventing ubiquitination-dependent activation (Akt) and degradation (p21 & p27) of Skp2 substrates with concomitant down-regulation of cellular Skp2 protein level (10 to 20 µ,M in HEK293T & PC3 cultures). Exhibits antiproliferation activity toward a panel of 8 cancer (IC50 from 1.22 to 10.5 µ,M), but not normal PNT1A epithelial or IMR90 fibroblast, lines and effectively reduces ALDH+ cancer stem cell (CSC, Cancer Initiating Cell) population in prostate cancer PC3 cultures (10 to 20 µ,M) by promoting p53-independent senescence and blocking Akt-dependent aerobic glycolysis. Exhibits good pharmacokinetic property (tmax = 1 h, t1/2 >6 h, Cmax >1 µ,M/plasma and >4 µ,M/tumor in 200 mm3 PC3 tumor-bearing mice, 80 mg/kg i.p.) and is efficacious in suppressing A549 and PC3 tumor growth in mice (40 to 80 mg/kg/d i.p.) in vivo., A cell-permeable benzothiazolylchromenone compound that disrupts Skp2-Skp1 interaction via direct Skp2 affinity binding and selectively prevents Skp2-, but not Fbw7- or beta-TrCP-, Skp1-Cullin-1-F-box (SFC) complex-mediated substrates ubiquitination, effectively preventing Skp2 substrates activation (Akt) and degradation (p21 & p27) with concomitant down-regulation of cellular Skp2 protein level (10 to 20 µ,M in HEK293T & PC3 cultures). Exhibits antiproliferation activity toward a panel of 8 cancer (IC50 from 1.22 to 10.5 µ,M) and reduces ALDH+ cancer stem cell population in PC3 cultures (10 to 20 µ,M). Exhibits good pharmacokinetic property and is efficacious in suppressing A549 and PC3 tumor growth in mice (40 to 80 mg/kg/d i.p.) in vivo.