title: Macrocyclic bisindolylmaleimides as inhibitors of protein kinase C and glycogen synthase kinase-3.
abstract: 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.
authors.affiliation: Drug Discovery, Johnson & Johnson Pharmaceutical Research & Development, Spring House, PA 19477-0776, USA. hzhang@prdus.jnj.com
authors.forename: Han-Cheng
authors.initials: HC
authors.lastname: Zhang
authors.forename: Kimberly B
authors.initials: KB
authors.lastname: White
authors.forename: Hong
authors.initials: H
authors.lastname: Ye
authors.forename: David F
authors.initials: DF
authors.lastname: McComsey
authors.forename: Claudia K
authors.initials: CK
authors.lastname: Derian
authors.forename: Michael F
authors.initials: MF
authors.lastname: Addo
authors.forename: Patricia
authors.initials: P
authors.lastname: Andrade-Gordon
authors.forename: Annette J
authors.initials: AJ
authors.lastname: Eckardt
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Conway
authors.forename: Lori
authors.initials: L
authors.lastname: Westover
authors.forename: Jun Z
authors.initials: JZ
authors.lastname: Xu
authors.forename: Richard
authors.initials: R
authors.lastname: Look
authors.forename: Keith T
authors.initials: KT
authors.lastname: Demarest
authors.forename: Stuart
authors.initials: S
authors.lastname: Emanuel
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Maryanoff
mesh_terms: 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
chemical_list: 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