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      Discovery of AZD8931, an Equipotent, Reversible Inhibitor of Signaling by EGFR, HER2, and HER3 Receptors

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          Abstract

          Deregulation of HER family signaling promotes proliferation and tumor cell survival and has been described in many human cancers. Simultaneous, equipotent inhibition of EGFR-, HER2-, and HER3-mediated signaling may be of clinical utility in cancer settings where the selective EGFR or HER2 therapeutic agents are ineffective or only modestly active. We describe the discovery of AZD8931 (2), an equipotent, reversible inhibitor of EGFR-, HER2-, and HER3-mediated signaling and the structure-activity relationships within this series. Docking studies based on a model of the HER2 kinase domain helped rationalize the increased HER2 activity seen with the methyl acetamide side chain present in AZD8931. AZD8931 exhibited good pharmacokinetics in preclinical species and showed superior activity in the LoVo tumor growth efficacy model compared to close analogues. AZD8931 is currently being evaluated in human clinical trials for the treatment of cancer.

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          Author and article information

          Journal
          ACS Medicinal Chemistry Letters
          ACS Med. Chem. Lett.
          American Chemical Society (ACS)
          1948-5875
          1948-5875
          July 15 2013
          August 08 2013
          June 03 2013
          August 08 2013
          : 4
          : 8
          : 742-746
          Affiliations
          [1 ]Centre de Recherches, AstraZeneca, Z.I. La Pompelle, B.P. 1050, Chemin de Vrilly, 51689 Reims, Cedex 2, France
          [2 ]Oncology iMed, AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom
          Article
          10.1021/ml400146c
          4027407
          24900741
          61a011d4-619d-4d8d-8aba-4639f1527854
          © 2013
          History

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