Macrocyclic bisindolylmaleimides as inhibitors of protein kinase C and glycogen synthase kinase-3.
Efficient methods were developed to synthesize a novel series of macrocyclic bisindolylmaleimides containing linkers with multiple heteroatoms. Potent inhibitors (single digit nanomolar IC(50)) for PKC-beta and GSK-3beta were identified, and compounds showed good selectivity over PKC-alpha, -gamma, -delta, -epsilon, and -zeta. Representative compound 5a also had high selectivity in a screening panel of 10 other protein kinases. In cell-based functional assays, several compounds effectively blocked interleukin-8 release induced by PKC-betaII and increased glycogen synthase activity by inhibiting GSK-3beta.
Zhang
Han-Cheng
HC
Drug Discovery, Johnson & Johnson Pharmaceutical Research & Development, Spring House, PA 19477-0776, USA. hzhang@prdus.jnj.com
White
Kimberly B
KB
Ye
Hong
H
McComsey
David F
DF
Derian
Claudia K
CK
Addo
Michael F
MF
Andrade-Gordon
Patricia
P
Eckardt
Annette J
AJ
Conway
Bruce R
BR
Westover
Lori
L
Xu
Jun Z
JZ
Look
Richard
R
Demarest
Keith T
KT
Emanuel
Stuart
S
Maryanoff
Bruce E
BE
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D002460:Cell Line; D003500:Cyclization; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D007527:Isoenzymes / Q000138:chemical synthesis / Q000494:pharmacology; D008301:Maleimides / Q000138:chemical synthesis* / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D064546:Protein Kinase C beta; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007211:Indoles; D007527:Isoenzymes; D008301:Maleimides; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D038362:Glycogen Synthase Kinase 3; C088060:bisindolylmaleimide