Highly selective inhibitors of protein kinases CLK and HIPK with the furo[3,2-b]pyridine core

Eur J Med Chem. 2021 Apr 5:215:113299. doi: 10.1016/j.ejmech.2021.113299. Epub 2021 Feb 18.

Abstract

The furo [3,2-b]pyridine motif represents a relatively underexplored central pharmacophore in the area of kinase inhibitors. Herein, we report flexible synthesis of 3,5-disubstituted furo [3,2-b]pyridines that relies on chemoselective couplings of newly prepared 5-chloro-3-iodofuro [3,2-b]pyridine. This methodology allowed efficient second-generation synthesis of the state-of-the-art chemical biology probe for CLK1/2/4 MU1210, and identification of the highly selective inhibitors of HIPKs MU135 and MU1787 which are presented and characterized in this study, including the X-ray crystal structure of MU135 in HIPK2. chemical biology probe.

Keywords: CLK; Furo[3,2-b]pyridine; HIPK; Inhibitor; Kinase; MU1210; MU135; MU1787.

MeSH terms

  • Animals
  • Carrier Proteins / antagonists & inhibitors*
  • Carrier Proteins / metabolism
  • Crystallography, X-Ray
  • Furans / chemical synthesis
  • Furans / metabolism
  • Furans / pharmacology*
  • Humans
  • MCF-7 Cells
  • Mice
  • Molecular Structure
  • Protein Binding
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein Serine-Threonine Kinases / metabolism
  • Pyridines / chemical synthesis
  • Pyridines / metabolism
  • Pyridines / pharmacology*
  • Structure-Activity Relationship

Substances

  • Carrier Proteins
  • Furans
  • Protein Kinase Inhibitors
  • Pyridines
  • HIPK2 protein, human
  • HIPK1 protein, human
  • Protein Serine-Threonine Kinases