Furo[3,2-b]pyridine: A Privileged Scaffold for Highly Selective Kinase Inhibitors and Effective Modulators of the Hedgehog Pathway

Angew Chem Int Ed Engl. 2019 Jan 21;58(4):1062-1066. doi: 10.1002/anie.201810312. Epub 2018 Dec 20.

Abstract

Reported is the identification of the furo[3,2-b]pyridine core as a novel scaffold for potent and highly selective inhibitors of cdc-like kinases (CLKs) and efficient modulators of the Hedgehog signaling pathway. Initially, a diverse target compound set was prepared by synthetic sequences based on chemoselective metal-mediated couplings, including assembly of the furo[3,2-b]pyridine scaffold by copper-mediated oxidative cyclization. Optimization of the subseries containing 3,5-disubstituted furo[3,2-b]pyridines afforded potent, cell-active, and highly selective inhibitors of CLKs. Profiling of the kinase-inactive subset of 3,5,7-trisubstituted furo[3,2-b]pyridines revealed sub-micromolar modulators of the Hedgehog pathway.

Keywords: biological activity; chemical probes; heterocycles; inhibitors; kinases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Cell Survival / drug effects
  • Furans / chemistry*
  • Hedgehog Proteins / chemistry*
  • Humans
  • Inhibitory Concentration 50
  • MCF-7 Cells
  • Molecular Structure
  • Protein Binding
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology
  • Pyridines / chemistry*
  • Small Molecule Libraries / chemical synthesis*
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology

Substances

  • Furans
  • Hedgehog Proteins
  • Protein Kinase Inhibitors
  • Pyridines
  • Small Molecule Libraries
  • furo(3,2-b)pyridine