Indolyl-naphthyl-maleimides as potent and selective inhibitors of protein kinase C-α/β

Bioorg Med Chem Lett. 2017 Feb 15;27(4):781-786. doi: 10.1016/j.bmcl.2017.01.038. Epub 2017 Jan 16.

Abstract

The indolyl-naphthyl maleimide 7 is a potent inhibitor of the classical PKC isotypes α,β and shows excellent selectivity over the novel PKC isotypes δ,ε,η,θ and other kinases belonging to the AGC family. The SAR around 7 as well as the physico-chemical characteristics of selected derivatives and their activity in T and B cell activation and proliferation assays are discussed.

Keywords: B-cell activation; Inhibitors; PKC alpha/beta; T-cell activation.

MeSH terms

  • B-Lymphocytes / cytology
  • B-Lymphocytes / drug effects*
  • B-Lymphocytes / metabolism
  • Binding Sites
  • Cell Proliferation / drug effects
  • Humans
  • Indoles / chemistry
  • Inhibitory Concentration 50
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / metabolism
  • Lymphocyte Activation / drug effects
  • Maleimides / chemical synthesis
  • Maleimides / chemistry*
  • Maleimides / pharmacology*
  • Molecular Docking Simulation
  • Naphthols / chemistry
  • Protein Binding
  • Protein Kinase C beta / antagonists & inhibitors*
  • Protein Kinase C beta / metabolism
  • Protein Kinase C-alpha / antagonists & inhibitors*
  • Protein Kinase C-alpha / metabolism
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology
  • Protein Structure, Tertiary
  • Structure-Activity Relationship
  • T-Lymphocytes / cytology
  • T-Lymphocytes / drug effects*
  • T-Lymphocytes / metabolism

Substances

  • Indoles
  • Isoenzymes
  • Maleimides
  • Naphthols
  • Protein Kinase Inhibitors
  • Protein Kinase C beta
  • Protein Kinase C-alpha