Mitigation of Acetylcholine Esterase Activity in the 1,7-Diazacarbazole Series of Inhibitors of Checkpoint Kinase 1

J Med Chem. 2015 Jun 25;58(12):5053-74. doi: 10.1021/acs.jmedchem.5b00464. Epub 2015 Jun 4.

Abstract

Checkpoint kinase 1 (ChK1) plays a key role in the DNA damage response, facilitating cell-cycle arrest to provide sufficient time for lesion repair. This leads to the hypothesis that inhibition of ChK1 might enhance the effectiveness of DNA-damaging therapies in the treatment of cancer. Lead compound 1 (GNE-783), the prototype of the 1,7-diazacarbazole class of ChK1 inhibitors, was found to be a highly potent inhibitor of acetylcholine esterase (AChE) and unsuitable for development. A campaign of analogue synthesis established SAR delineating ChK1 and AChE activities and allowing identification of new leads with improved profiles. In silico docking using a model of AChE permitted rationalization of the observed SAR. Compounds 19 (GNE-900) and 30 (GNE-145) were identified as selective, orally bioavailable ChK1 inhibitors offering excellent in vitro potency with significantly reduced AChE activity. In combination with gemcitabine, these compounds demonstrate an in vivo pharmacodynamic effect and are efficacious in a mouse p53 mutant xenograft model.

MeSH terms

  • Acetylcholinesterase / chemistry
  • Acetylcholinesterase / metabolism*
  • Acetylcholinesterase / pharmacokinetics
  • Acetylcholinesterase / therapeutic use
  • Animals
  • Aza Compounds / chemistry
  • Aza Compounds / pharmacokinetics
  • Aza Compounds / pharmacology
  • Aza Compounds / therapeutic use
  • Carbazoles / chemistry*
  • Carbazoles / pharmacology*
  • Cell Line, Tumor
  • Checkpoint Kinase 1
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacokinetics
  • Cholinesterase Inhibitors / pharmacology
  • Cholinesterase Inhibitors / therapeutic use
  • Crystallography, X-Ray
  • Dogs
  • Humans
  • Mice
  • Mice, Nude
  • Models, Molecular
  • Neoplasms / drug therapy
  • Neoplasms / enzymology
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use
  • Protein Kinases / chemistry
  • Protein Kinases / metabolism*
  • Rats

Substances

  • Aza Compounds
  • Carbazoles
  • Cholinesterase Inhibitors
  • Protein Kinase Inhibitors
  • Protein Kinases
  • CHEK1 protein, human
  • Checkpoint Kinase 1
  • Chek1 protein, mouse
  • Chek1 protein, rat
  • Acetylcholinesterase

Associated data

  • PDB/4QYH
  • PDB/4RVK
  • PDB/4RVL
  • PDB/4RVM