Macrocyclic bisindolylmaleimides as inhibitors of protein kinase C and glycogen synthase kinase-3

  • Bioorg Med Chem Lett. 2003 Sep 15;13(18):3049-53. doi: 10.1016/s0960-894x(03)00644-9.
Han-Cheng Zhang  1 ,  Kimberly B White ,  Hong Ye ,  David F McComsey ,  Claudia K Derian ,  Michael F Addo ,  Patricia Andrade-Gordon ,  Annette J Eckardt ,  Bruce R Conway ,  Lori Westover ,  Jun Z Xu ,  Richard Look ,  Keith T Demarest ,  Stuart Emanuel ,  Bruce E Maryanoff
Affiliations
  • 1. Drug Discovery, Johnson & Johnson Pharmaceutical Research & Development, Spring House, PA 19477-0776, USA. [email protected]
PMID: 12941331 DOI: 10.1016/s0960-894x(03)00644-9
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.