2,6-Diamino-N-([1-(1-oxotridecyl)-2-piperidinyl]methyl)hexanamide (NPC 15437): A selective inhibitor of protein kinase C

Autor: Sullivan, J. P., Connor, J. R., Shearer, B. G., Burch, R. M.
Zdroj: Inflammation Research; September 1991, Vol. 34 Issue: 1-2 p142-144, 3p
Abstrakt: NPC 15437 inhibited protein kinase C (PKC) activity and [3H]phorbol 12,13-dibutyrate (PDBu) binding to the enzyme in a concentration-dependent manner (IC50 values, 19±2 μM and 23±4 μM, respectively). No inhibition of cAMP-dependent protein kinase A (PKA) or calcium/calmodulin-dependent myosin light chain kinase (MLCK) was observed. A detailed kinetic analysis of the interaction of NPC 15437 and a homogeneous preparation of PKC-alpha revealed a competitive type of inhibition with respect to activation of the enzyme by both phorbol 12-myristate 13-acetate (PMA) (Ki=5±3 μM) and phosphatidylserine (PS) (Ki=12±4 μM). Mixed inhibition (predominantly of the non-competitive type), with respect to activation of the enzyme by calcium, was also observed. These studies indicate that NPC 15437 is a selective inhibitor of PKC, interacting at the regulatory region of the molecule. NPC 15437 inhibited phorbol ester-induced ear edema in mouse (IC50=175 μg/ear) demonstrating the ability of NPC 15437 to inhibit PKC-mediated activity in intact cells.
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