p38 MAP Kinase Inhibitor XIX; Skepinone-L

General description

A cell-permeable phenylamino-dibenzosuberone-diol with a rigid molecular structure specifically designed to target p38A & p38β hydrophobic region I whose access is possible due to a small gatekeeper amino acid (Thr106 in human p38A/β ), but not in other kinases with bulky entrance-blocking gatekeeper residues. Shown to selectively inhibit p38A (IC₅₀ = 5 nM; [ATP] = 100 µM) and p38β (97% inhibition at1 µM), while being less effective against JNK3, SLK, or CAMK2D (67%, 61%, and 57% inhibition, respectively, at 1 µM) and exhibiting little or no potency toward 328 other kinase constructs (IC₅₀ >1 µM). Likewise, binding studies reveal selective affinity toward p38A (K_d = 1.5 nM) and p38β, but not 400 other kinase constructs, including p38δ, p38γ, 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-A in THP-1 cultures (80 nM). Unlike BIRB 796 (2 µM; Cat. No. 506172), Skepinone-L does not inhibit JNK-mediated c-Jun Ser63 phosphorylation upon TNF-A 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 µM; 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-A 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 p38A & p38β, but not in other kinases with bulky entrance-blocking gatekeeper residues. Shown to selectively inhibit p38A (IC₅₀ = 5 nM; [ATP] = 100 µM) and p38β (97% inhibition at1 µM), while exhibiting little affinity toward 400 other kinase constructs, including p38δ, p38γ, 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-A 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-A production upon LPS (Cat. No. 437625) challenge (by 77%; 3 mg/kg p.o.) in vivo.

Legal Information

CALBIOCHEM is a registered trademark of Merck KGaA, Darmstadt, Germany

Other Notes

Koeberle, S.C., et al. 2012. J. Med. Chem.55, 5868.Koeberle, S.C., et al. 2011. Nat. Chem. Biol.8, 141.

Packaging

5 mg in Glass bottle

Packaged under inert gas

Reconstitution

Following reconstitution, aliquot and freeze (-20°C). Stock solutions are stable for up to 6 months at -20°C.

Warning

Toxicity: Standard Handling (A)