4-benzimidazolyl-3-phenylbutanoic acids as novel PIF-pocket-targeting allosteric inhibitors of protein kinase PKCζ

J Med Chem. 2011 Oct 13;54(19):6714-23. doi: 10.1021/jm2005892. Epub 2011 Sep 14.

Abstract

Protein kinase inhibitors with an allosteric mode of action are expected to reach, in many cases, higher selectivity for the target enzyme than ATP-competitive compounds. Therefore, basic research is aiming at identifying and establishing novel sites on the catalytic domain of protein kinases which might be targeted by allosteric inhibitors. We previously published the first structure-activity relationships (SARs) for allosteric activators of protein kinase PDK1. Here, we present the design, synthesis, and SAR data on a series of novel compounds, 4-benzimidazolyl-3-phenylbutanoic acids, that inhibit the atypical protein kinace C (PKC) ζ via binding to the PIF-pocket. Key positions were identified in the compounds that can be modified to increase potency and selectivity. Some congeners showed a high selectivity toward PKCζ, lacking inhibition of the most closely related isoform, PKCι, and of further AGC kinases. Furthermore, evidence is provided that these compounds are also active toward cellular PKCζ without loss of potency compared to the cell-free assay.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3-Phosphoinositide-Dependent Protein Kinases
  • Allosteric Regulation
  • Binding Sites
  • Butyrates / chemical synthesis*
  • Butyrates / chemistry
  • Butyrates / pharmacology
  • Cell-Free System
  • Humans
  • NF-kappa B / metabolism
  • Protein Binding
  • Protein Kinase C / antagonists & inhibitors*
  • Protein Kinase C / metabolism*
  • Protein Serine-Threonine Kinases / metabolism
  • Recombinant Proteins / antagonists & inhibitors
  • Signal Transduction / drug effects
  • Stereoisomerism
  • Structure-Activity Relationship
  • U937 Cells

Substances

  • Butyrates
  • NF-kappa B
  • Recombinant Proteins
  • protein kinase N
  • 3-Phosphoinositide-Dependent Protein Kinases
  • PDPK1 protein, human
  • Protein Serine-Threonine Kinases
  • protein kinase C zeta
  • Protein Kinase C