Back to your search result

Description

A cell-permeable phenylamino-dibenzosuberone-diol with a rigid molecular structure specifically designed to target p38&alpha, & p38&beta, hydrophobic region I whose access is possible due to a small gatekeeper amino acid (Thr106 in human p38&alpha,/&beta, ), but not in other kinases with bulky entrance-blocking gatekeeper residues. Shown to selectively inhibit p38&alpha, (IC50 = 5 nM, [ATP] = 100 microM) and p38&beta, (97% inhibition at1 microM), while being less effective against JNK3, SLK, or CAMK2D (67%, 61%, and 57% inhibition, respectively, at 1 microM) and exhibiting little or no potency toward 328 other kinase constructs (IC50 >1 microM). Likewise, binding studies reveal selective affinity toward p38&alpha, (Kd = 1.5 nM) and p38&beta,, but not 400 other kinase constructs, including p38&delta,, p38&gamma,, Erk1/2/3/4/5/8, JNK1/2/3, and MEK1/2/3/4/6. Shown to prevent cellular HSP27 Ser82 phosphorylation upon p38 activation by Anisomycin (Cat. No. ) in HeLa (IC50 = 25 nM) or by TNF-&alpha, in THP-1 cultures (80 nM). Unlike BIRB 796 (2 microM, Cat. No. 506172), Skepinone-L does not inhibit JNK-mediated c-Jun Ser63 phosphorylation upon TNF-&alpha, stimulation in THP-1 cells, nor does Skepinone-L affect ERK-dependent CREB Ser133 phosphorylation in THP-1 upon PMA (Cat. No. 506172) treatment, whereas SB 203580 (4 microM, Cat. Nos. 559389, 559395, and 559398) is shown to inhibit. Oral administration to D-Gal- (Cat. No. 34539) sensitized mice 1h prior to 90 min LPS (Cat. No. 437625) challenge greatly reduces plasma TNF-&alpha, production (by 77%, plasma [inhibitor] = 240 nM, 3 mg/kg p.o.) in vivo., A cell-permeable phenylamino-dibenzosuberone-diol with a rigid molecular structure specifically designed to target hydrophobic region I in p38&alpha, & p38&beta,, but not in other kinases with bulky entrance-blocking gatekeeper residues. Shown to selectively inhibit p38&alpha, (IC50 = 5 nM, [ATP] = 100 microM) and p38&beta, (97% inhibition at1 microM), while exhibiting little affinity toward 400 other kinase constructs, including p38&delta,, p38&gamma,, Erk1/2/3/4/5/8, JNK1/2/3, and MEK1/2/3/4/6. Shown to prevent cellular HSP27 Ser82 phosphorylation upon p38 activation by Anisomycin (Cat. No. 176880) in HeLa (IC50 = 25 nM) or by TNF-&alpha, in THP-1 cultures. Unlike the ATP-binding site-targeting BIRB 796 (Cat. No. 506172) and SB 203580 (Cat. Nos. 559389, 559395, and 559398), Skepinone-L does not inhibit JNK-mediated c-Jun or ERK-dependent CREB phosphorylation in THP-1 cultures. Oral administration to D-Gal- (Cat. No. 34539) sensitized mice is reported to greatly reduce plasma TNF-&alpha, production upon LPS (Cat. No. 437625) challenge (by 77%, 3 mg/kg p.o.) in vivo.