Design of potent and selective inhibitors to overcome clinical anaplastic lymphoma kinase mutations resistant to crizotinib

J Med Chem. 2014 Feb 27;57(4):1170-87. doi: 10.1021/jm401805h. Epub 2014 Feb 6.


Crizotinib (1), an anaplastic lymphoma kinase (ALK) receptor tyrosine kinase inhibitor approved by the U.S. Food and Drug Administration in 2011, is efficacious in ALK and ROS positive patients. Under pressure of crizotinib treatment, point mutations arise in the kinase domain of ALK, resulting in resistance and progressive disease. The successful application of both structure-based and lipophilic-efficiency-focused drug design resulted in aminopyridine 8e, which was potent across a broad panel of engineered ALK mutant cell lines and showed suitable preclinical pharmacokinetics and robust tumor growth inhibition in a crizotinib-resistant cell line (H3122-L1196M).

MeSH terms

  • Anaplastic Lymphoma Kinase
  • Crizotinib
  • Drug Resistance, Neoplasm / genetics*
  • Humans
  • Point Mutation*
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrazoles / pharmacology*
  • Pyridines / pharmacology*
  • Receptor Protein-Tyrosine Kinases / genetics*


  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyridines
  • Crizotinib
  • ALK protein, human
  • Anaplastic Lymphoma Kinase
  • Receptor Protein-Tyrosine Kinases