Structure- and reactivity-based development of covalent inhibitors of the activating and gatekeeper mutant forms of the epidermal growth factor receptor (EGFR).

@article{Ward2013StructureAR,
  title={Structure- and reactivity-based development of covalent inhibitors of the activating and gatekeeper mutant forms of the epidermal growth factor receptor (EGFR).},
  author={Richard A. Ward and Mark John. Anderton and Susan Elizabeth Ashton and Paul A. Bethel and Matthew R. Box and Sam Butterworth and Nicola Colclough and Christopher G Chorley and Claudio Edmundo Chuaqui and Darren A. E. Cross and Les A. Dakin and Judit {\'E}. Debreczeni and Cath A Eberlein and Maurice Raymond Verschoyle Finlay and George Birkbeck Norman Hill and M. Thomas Madison Grist and Teresa C.M. Klinowska and Clare D Lane and Scott Graham Martin and Jonathon P. Orme and Peter J. Smith and Fengjiang Wang and Michael J. Waring},
  journal={Journal of medicinal chemistry},
  year={2013},
  volume={56 17},
  pages={
          7025-48
        }
}
A novel series of small-molecule inhibitors has been developed to target the double mutant form of the epidermal growth factor receptor (EGFR) tyrosine kinase, which is resistant to treatment with gefitinib and erlotinib. Our reported compounds also show selectivity over wild-type EGFR. Guided by molecular modeling, this series was evolved to target a cysteine residue in the ATP binding site via covalent bond formation and demonstrates high levels of activity in cellular models of the double… CONTINUE READING
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