Synthesis and biological evaluation of analogues of the kinase inhibitor nilotinib as Abl and Kit inhibitors.

Medicinal Chemistry


The importance of the trifluoromethyl group in the polypharmacological profile of nilotinib was investigated. Molecular editing of nilotinib led to the design, synthesis and biological evaluation of analogues where the trifluoromethyl group was replaced by a proton, fluorine and a methyl group. While these analogues were less active than nilotinib toward Abl, their activity toward Kit was comparable, with the monofluorinated analogue being the most active. Docking of nilotinib and of analogues 2a-c to the binding pocket of Abl and of Kit showed that the lack of shape complementarity in Kit is compensated by the stabilizing effect from its juxtamembrane region.


Duveau, Damien; Hu, Xin; Walsh, Martin J; Shukla, Suneet; Skoumbourdis, Amanda P; Boxer, Matthew B; Ambudkar, Suresh V; Shen, Min; Thomas, Craig;


  • Catalytic Domain
  • Drug Design
  • Enzyme Activation/ drug effects
  • Fluorine/ chemistry
  • Methane/ chemistry
  • Models, Molecular
  • Molecular Structure
  • Oncogene Proteins v-abl/ antagonists & inhibitors
  • Protein Kinase Inhibitors/ chemical synthesis
  • Protein Kinase Inhibitors/ chemistry
  • Protein Kinase Inhibitors/ pharmacology
  • Protein-Tyrosine Kinases/ antagonists & inhibitors
  • Proto-Oncogene Proteins c-kit/ antagonists & inhibitors
  • Pyrimidines/ chemical synthesis
  • Pyrimidines/ chemistry
  • Pyrimidines/ pharmacology

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