Identification of novel aminothiazole and aminothiadiazole conjugated cyanopyridines as selective CHK1 inhibitors

Eur J Med Chem. 2015 Mar 6:92:459-70. doi: 10.1016/j.ejmech.2015.01.019. Epub 2015 Jan 10.

Abstract

Inhibitors of checkpoint kinase 1 (CHK1) are of current interest as potential anti-tumor agents. Novel series of cyanopyridyl-aminothiadiazoles (synthesized from reaction of 1-(3-cyano-4,6-diphenylpyridin-2-yl)-3-phenylthiourea (14) with hydrazonoyl halides) and cyanopyridyl-aminothiazolyl-thiadiazoles (synthesized from treatment of 14 with ethyl chloroacetate followed by reaction of the obtained cyanopyridyl-aminothiazole with hydrazonoyl halides) were synthesized and evaluated for their CHK1 inhibitory potential using a cell-based assay cascade. The tested compounds exhibited a potent and selective CHK1 inhibitory activity at nanomolar levels that reflected their ability to abrogate cell cycle arrest and potentiate the cytotoxic effect of the genotoxic drug gemcitabine in colon cancer cells. Molecular modeling simulation revealed that, the most active compound 28a docked well into the enzyme active site and their complex is stabilized by a key H-bonding with the backbone amide of Cys-87 as well as multiple favorable hydrophobic interactions with different hydrophobic binding regions of the enzyme.

Keywords: 1,3,4-Thiadiazoles; 2-Aminocyanopyridine; Hydrazonoyl halides; Selective CHK1 inhibitors.

Publication types

  • Retracted Publication

MeSH terms

  • Checkpoint Kinase 1
  • Dose-Response Relationship, Drug
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinases / metabolism*
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Structure-Activity Relationship
  • Thiadiazoles / chemistry
  • Thiadiazoles / pharmacology*

Substances

  • Protein Kinase Inhibitors
  • Pyridines
  • Thiadiazoles
  • 2-amino-1,3,4-thiadiazole
  • Protein Kinases
  • CHEK1 protein, human
  • Checkpoint Kinase 1