N-(1H-Pyrazol-3-yl)quinazolin-4-amines as a novel class of casein kinase 1δ/ε inhibitors: Synthesis, biological evaluation and molecular modeling studies

Bioorg Med Chem Lett. 2017 Jun 15;27(12):2663-2667. doi: 10.1016/j.bmcl.2017.04.080. Epub 2017 Apr 27.

Abstract

Described herein is the design, synthesis and biological evaluation of a series of N-(1H-pyrazol-3-yl)quinazolin-4-amines against a panel of eight disease relevant protein kinases. The kinase inhibition results indicated that two compounds inhibited casein kinase 1δ/ε (CK1δ/ε) with some selectivity over related kinases, namely CDK5/p25, GSK-3α/β, and DYRK1A. Docking studies with 3c and 3d revealed the key interactions with desired amino acids in the ATP binding site of CK1δ. Furthermore, compound 3c also elicited selective cytotoxic activity against the pancreas ductal adenocarcinoma (PANC-1) cell line. Taken together, the results of this study establish N-(1H-pyrazol-3-yl)quinazolin-4-amines especially 3c and 3d as valuable lead molecules with great potential for CK1δ/ε inhibitor development targeting neurodegenerative disorders and cancer.

Keywords: Cancer; Casein kinase 1δ/ε; MTT assay; Neurodegenerative diseases; Protein kinases; Quinazolines.

MeSH terms

  • Casein Kinase 1 epsilon / antagonists & inhibitors*
  • Casein Kinase 1 epsilon / metabolism
  • Casein Kinase Idelta / antagonists & inhibitors*
  • Casein Kinase Idelta / metabolism
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrazoles / chemical synthesis
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology*
  • Quinazolines / chemical synthesis
  • Quinazolines / chemistry
  • Quinazolines / pharmacology*
  • Structure-Activity Relationship

Substances

  • Protein Kinase Inhibitors
  • Pyrazoles
  • Quinazolines
  • Casein Kinase 1 epsilon
  • Casein Kinase Idelta