2. Academic Validation
  3. Macrocyclic bisindolylmaleimides as inhibitors of protein kinase C and glycogen synthase kinase-3

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

Affiliation

  • 1 Drug Discovery, Johnson & Johnson Pharmaceutical Research & Development, Spring House, PA 19477-0776, USA. hzhang@prdus.jnj.com
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.

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