Isoenzyme specificity of bisindolylmaleimides, selective inhibitors of protein kinase C.
The protein kinase C (PKC) family of isoenzymes is believed to mediate a wide range of signal-transduction pathways in many different cell types. A series of bisindolylmaleimides have been evaluated as inhibitors of members of the conventional PKC family (PKCs-alpha, -beta, -gamma) and of a representative of the new, Ca(2+)-independent, PKC family, PKC-epsilon. In contrast with the indolocarbazole staurosporine, all the bisindolylmaleimides investigated showed slight selectivity for PKC-alpha over the other isoenzymes examined. In addition, bisindolylmaleimides bearing a conformationally restricted side-chain were less active as inhibitors of PKC-epsilon. Most noticeable of these was Ro 32-0432, which showed a 10-fold selectivity for PKC-alpha and a 4-fold selectivity for PKC-beta I over PKC-epsilon.
Research Centre, Roche Products Ltd., Welwyn Garden City, Herts, U.K.
S E
SE
Wilkinson
P J
PJ
Parker
J S
JS
Nixon
D000255:Adenosine Triphosphate / Q000378:metabolism; D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D001921:Brain / Q000201:enzymology; D007211:Indoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008301:Maleimides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008968:Molecular Conformation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D051381:Rats; D019311:Staurosporine; D013329:Structure-Activity Relationship
D000470:Alkaloids; D007211:Indoles; D007527:Isoenzymes; D008301:Maleimides; D000255:Adenosine Triphosphate; D011493:Protein Kinase C; D019311:Staurosporine; C064758:Ro 31-8220; C064755:Ro 31-7549