ALK inhibitors of bis-ortho-alkoxy-para-piperazinesubstituted-pyrimidines and -triazines for cancer treatment

Arch Pharm Res. 2014;37(9):1130-8. doi: 10.1007/s12272-013-0323-z. Epub 2014 Jan 21.

Abstract

Syntheses of various bis-ortho-alkoxy-para-piperazineanilino-pyrimidines and -triazines of KRCA-0008 analogs are described and their structure-activity-relationship to anaplastic lymphoma kinase (ALK) is discussed. 5-trifluoromethyl-2,4-pyrimidine analog (2) seems to be most potent in both biochemical and cellular assay in this study, however it shows inferior mice xenograft activity to Crizotinib presumably due to its sub-optimal PK parameters. 4,6-disubstituted pyrimidine and 2,4-disubstituted triazine derivatives of KRCA-0008 are less potent or inactive to ALK wt., and this observation is explained with their molecular modeling compared to KRCA-0008.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Anaplastic Lymphoma Kinase
  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / enzymology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Female
  • Half-Life
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / enzymology
  • Mice, Nude
  • Molecular Docking Simulation
  • Mutation
  • Oncogene Proteins, Fusion / antagonists & inhibitors*
  • Oncogene Proteins, Fusion / chemistry
  • Oncogene Proteins, Fusion / genetics
  • Oncogene Proteins, Fusion / metabolism
  • Piperazines / chemistry
  • Piperazines / pharmacokinetics
  • Piperazines / pharmacology
  • Piperazines / therapeutic use*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use*
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacokinetics
  • Pyrimidines / pharmacology
  • Pyrimidines / therapeutic use
  • Rats, Sprague-Dawley
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Receptor Protein-Tyrosine Kinases / chemistry
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Structure-Activity Relationship
  • Triazines / chemistry
  • Triazines / pharmacokinetics
  • Triazines / pharmacology
  • Triazines / therapeutic use
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • 1,1'-((((5-(trifluoromethyl)pyrimidine-2,4-diyl)bis(azanediyl))bis(3-methoxy-4,1-phenylene))bis(piperazine-4,1-diyl))bis(ethan-1-one)
  • Antineoplastic Agents
  • EML4-ALK fusion protein, human
  • Oncogene Proteins, Fusion
  • Piperazines
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Triazines
  • ALK protein, human
  • Alk protein, mouse
  • Alk protein, rat
  • Anaplastic Lymphoma Kinase
  • Receptor Protein-Tyrosine Kinases