Selective inhibition of eukaryote protein kinases by anti-inflammatory triterpenoids

The ursane triterpenoid alpha-amyrin and the lupane triterpenoid lupeol are potent inhibitors of the catalytic subunit (cAK) of rat liver cyclic AMP-d ependent protein kinase (PKA) with IC50 values of 8 and 5 mu M, respectivel y. The palmitate and linoleate esters of alpha-amyrin and lupeol are also p otent inhibitors of cAK (IC50 values in the range of 4-9 mu M) alpha-amyrin , lupeol and lupeol linoleate are much less potent as inhibitors of rat bra in Ca2+- and phospholipid-dependent protein kinase (PKC) (IC50 values 32, 8 2 and 35 mu M; respectively) and alpha-amyrin linoleate and the palmitate e sters of lupeol and alpha-amyrin are ineffective or very poor inhibitors of this protein kinase. These compounds are very poor or ineffective as inhib itors of chicken gizzard calmodulin-dependent myosin light chain kinase (ML CK). alpha-Amyrin inhibits plant Ca2+-dependent protein kinase (CDPK) (IC50 52 mu M) but lupeol and the triterpenoid esters tested are ineffective, al pha-Amyrin and the linoleate and palmitate esters of alpha-amyrin and lupeo l inhibit cAK in a fashion that is competitive with respect to both peptide substrate and ATP (K-i values in the range 2-6 mu M). However, while lupeo l is competitive with respect to ATP it is apparently non-competitive with respect to peptide substrate. alpha-Amyrin also inhibits CDPK competitively and alpha-amyrin, lupeol and lupeol linoleate are competitive inhibitors o f PKC. alpha-Amyrin and the palmitate esters of lupeol and alpha-amyrin are competitive inhibitors of the potato high affinity cyclic AMP-binding phos phatase (Pase) but lupeol inhibits the Pase noncompetitively. These hydroph obic triterpenoids are further examples of anti-inflammatory triterpenoids that are cAK inhibitors.