Blog
About

4
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: not found

      Trisubstituted Pyridinylimidazoles as Potent Inhibitors of the Clinically Resistant L858R/T790M/C797S EGFR Mutant: Targeting of Both Hydrophobic Regions and the Phosphate Binding Site.

      Read this article at

      ScienceOpenPublisherPubMed
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Inhibition of the epidermal growth factor receptor represents one of the most promising strategies in the treatment of lung cancer. Acquired resistance compromises the clinical efficacy of EGFR inhibitors during long-term treatment. The recently discovered EGFR-C797S mutation causes resistance against third-generation EGFR inhibitors. Here we present a rational approach based on extending the inhibition profile of a p38 MAP kinase inhibitor toward mutant EGFR inhibition. We used a privileged scaffold with proven cellular potency as well as in vivo efficacy and low toxicity. Guided by molecular modeling, we synthesized and studied the structure-activity relationship of 40 compounds against clinically relevant EGFR mutants. We successfully improved the cellular EGFR inhibition down to the low nanomolar range with covalently binding inhibitors against a gefitinib resistant T790M mutant cell line. We identified additional noncovalent interactions, which allowed us to develop metabolically stable inhibitors with high activities against the osimertinib resistant L858R/T790M/C797S mutant.

          Related collections

          Author and article information

          Journal
          J. Med. Chem.
          Journal of medicinal chemistry
          American Chemical Society (ACS)
          1520-4804
          0022-2623
          Jul 13 2017
          : 60
          : 13
          Affiliations
          [1 ] Institute of Pharmaceutical Sciences, Pharmaceutical and Medicinal Chemistry, Eberhard Karls University Tübingen , Auf der Morgenstelle 8, 72076 Tübingen, Germany.
          [2 ] Faculty of Chemistry and Chemical Biology, TU Dortmund University , Otto-Hahn-Straße 4a, 44227 Dortmund, Germany.
          Article
          10.1021/acs.jmedchem.7b00316
          28603991

          Comments

          Comment on this article