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Beschreibung

A cell-permeable hydroxyphenyl-propylidene-benzohydrazide compound that acts as a potent, ATP-competitive (Ki = 0.3 microM), and highly isoform-selective PIM inhibitor (IC50 = 2.5, 2.5, and 0.047 microM against PIM1, PIM2, and PIM3, respectively, [ATP] = 10 microM), while affecting CK2&alpha,2 only at much higher concentrations (IC50 = 5 microM, [ATP] = 10 microM) and exhibiting little or no activity against a panel of 258 other kinases (<40% inhibition at 5 microM). Shown to inhibit PIM3-dependent STAT3 Tyr705 phosphorylation in DU-145 prostate cancer and MiaPaCa2 pancreatic cancer cells (by 73% and 83%, respectively, 10 microM for 18 h), while displaying little effect toward STAT3 Tyr694 phosphoylation in 22RV1 cultures., A cell-permeable hydroxyphenyl-propylidene-benzohydrazide compound that acts as a potent, ATP-competitive (Ki = 0.3 microM), and highly isoform-selective PIM inhibitor (IC50 = 2.5, 2.5, and 0.047 microM against PIM1, PIM2, and PIM3, respectively, with PIMtide as substrate, [ATP] = 10 microM), while affecting CK2&alpha,2 only at much higher concentrations (IC50 = 5 microM, [ATP] = 10 microM) and exhibiting little or no activity against a panel of 258 other kinases (<40% inhibition, [M-110] = 5 microM). M-100 treatment (10 microM for 18 hr) is shown to inhibit both basal (by 73% and 83% of DMSO control in DU-145 prostate cancer and MiaPaCa2 pancreatic cancer cells, respectively) and IL-6-stimulated (by 69% of DMSO control in DU-145 cells) STAT3 phosphorylation on Tyr705, while displaying little effect toward Tyr694 phosphoylation (in 22RV1 cultures). Isoform-specific knockdowns in DU-145 cells likewise identify PIM-3, but not PIM-1 or -2, as the kinase responsible for cellular STAT3 Tyr705 phosphorylation.