2,6-Diamino-N-([1-oxotridecyl)-2-piperidinyl]methyl)hexanamide (NPC 15437): a selective inhibitor of protein kinase C.
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 microM and 23 +/- 4 microM, 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 microM) and phosphatidylserine (PS) (Ki = 12 +/- 4 microM). 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 micrograms/ear) demonstrating the ability of NPC 15437 to inhibit PKC-mediated activity in intact cells.
Sullivan
J P
JP
Nova Pharmaceutical Corporation, Baltimore, Maryland 21224.
Connor
J R
JR
Shearer
B G
BG
Burch
R M
RM
D000818:Animals; D002118:Calcium / Q000502:physiology; D002460:Cell Line; D004487:Edema / Q000517:prevention & control; D051379:Mice; D009219:Myosin-Light-Chain Kinase / Q000378:metabolism; D010718:Phosphatidylserines / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*
D010718:Phosphatidylserines; D010880:Piperidines; C069701:NPC 15437; D011493:Protein Kinase C; D009219:Myosin-Light-Chain Kinase; D002118:Calcium