Conformation-Selective Analogues of Dasatinib Reveal Insight into Kinase Inhibitor Binding and Selectivity

ACS Chem Biol. 2016 May 20;11(5):1296-304. doi: 10.1021/acschembio.5b01018. Epub 2016 Mar 1.


In the kinase field, there are many widely held tenets about conformation-selective inhibitors that have yet to be validated using controlled experiments. We have designed, synthesized, and characterized a series of kinase inhibitor analogues of dasatinib, an FDA-approved kinase inhibitor that binds the active conformation. This inhibitor series includes two Type II inhibitors that bind the DFG-out inactive conformation and two inhibitors that bind the αC-helix-out inactive conformation. Using this series of compounds, we analyze the impact that conformation-selective inhibitors have on target binding and kinome-wide selectivity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Chickens
  • Dasatinib / analogs & derivatives*
  • Dasatinib / pharmacology*
  • Drug Design*
  • Humans
  • Molecular Docking Simulation
  • Protein Binding
  • Protein Conformation
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinases / chemistry
  • Protein Kinases / metabolism*


  • Protein Kinase Inhibitors
  • Protein Kinases
  • Dasatinib