Novel, potent and selective inhibitors of protein kinase C show oral anti-inflammatory activity

Drugs Exp Clin Res. 1991;17(8):389-93.


Clarification of the precise role of protein kinase C (PKC) in cellular functional responses has been hampered by a lack of potent, selective inhibitors. The structural lead provided by staurosporine, a potent but non-selective protein kinase (PK) inhibitor, was used to derive a series of bis(indolyl)maleimides of which the most potent, Ro 31-8425 (I50: PKC = 8 nM) showed 350-fold selectivity for PKC over cAMP-dependent protein kinase. Ro 31-8425 antagonised cellular processes triggered by phorbol esters (potent, specific PKC activators) and inhibited the allogeneic mixed lymphocyte reaction, suggesting a role for PKC in T-cell activation. Methylation of the primary amine in Ro 31-8425 produced an analogue. Ro 31-8830 which, when administered orally, produced a dose-dependent inhibition of a phorbol ester-induced paw oedema in mice (minimum effective dose = 15 mg/kg). Ro 31-8830 also selectively inhibited the secondary inflammation in a developing adjuvant arthritis model in the rat. The results presented here suggest that these selective inhibitors of PKC may have therapeutic value in the treatment of T-cell-mediated autoimmune diseases.

MeSH terms

  • Administration, Oral
  • Animals
  • Anti-Inflammatory Agents
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Arthritis, Experimental / drug therapy
  • Female
  • Indoles / pharmacology
  • Male
  • Maleimides / pharmacology
  • Mice
  • Phorbol Esters / pharmacology
  • Protein Kinase C / antagonists & inhibitors*
  • Rats


  • Anti-Inflammatory Agents
  • Anti-Inflammatory Agents, Non-Steroidal
  • Indoles
  • Maleimides
  • Phorbol Esters
  • Ro 31-8425
  • Ro 31-8830
  • Protein Kinase C