Novel bis-ortho-alkoxy-para-piperazinesubstituted-2,4-dianilinopyrimidines (KRCA-0008) as potent and selective ALK inhibitors for anticancer treatment

Bioorg Med Chem Lett. 2013 Nov 15;23(22):6192-6. doi: 10.1016/j.bmcl.2013.08.090. Epub 2013 Sep 4.

Abstract

The synthesis of bis-ortho-alkoxy-para-piperazinesubstituted-2,4-dianilinopyrimidines is described and their structure-activity-relationship to anaplastic lymphoma kinase (ALK) is presented. KRCA-0008 is selective and potent to ALK and Ack1, and displays drug-like properties without hERG liability. KRCA-0008 demonstrates in vivo efficacy comparable to Crizotinib in xenograft mice model.

Keywords: ACK1; ALK; Diaminopyrimidine; Inhibitors; Kinases; N-Acetylpiperidine; NSCLC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anaplastic Lymphoma Kinase
  • Animals
  • Cell Line, Tumor
  • Crizotinib
  • Disease Models, Animal
  • Lung Neoplasms / drug therapy
  • Mice
  • Piperazines / chemistry
  • Piperazines / pharmacokinetics
  • Piperazines / pharmacology*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrazoles / pharmacology
  • Pyridines / pharmacology
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacokinetics
  • Pyrimidines / pharmacology*
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Structure-Activity Relationship
  • Xenograft Model Antitumor Assays

Substances

  • Piperazines
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyridines
  • Pyrimidines
  • Crizotinib
  • Alk protein, mouse
  • Anaplastic Lymphoma Kinase
  • Receptor Protein-Tyrosine Kinases