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

Abstract

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.

• Authors: J P Sullivan, J R Connor, B G Shearer, R M Burch
• Journal: Agents and actions (Agents Actions) Vol. 34 Issue 1-2 Pg. 142-4 (Sep 1991) ISSN: 0065-4299 [Print] Switzerland
• PMID: 1793019 (Publication Type: Journal Article)

Chemical References

• Phosphatidylserines
• Piperidines
• NPC 15437
• Protein Kinase C
• Myosin-Light-Chain Kinase
• Calcium

Topics

• Animals
• Calcium (physiology)
• Cell Line
• Edema (prevention & control)
• Mice
• Myosin-Light-Chain Kinase (metabolism)
• Phosphatidylserines (metabolism)
• Piperidines (pharmacology)
• Protein Kinase C (antagonists & inhibitors)