2. Academic Validation
  3. Discovery of a potent, selective, and orally active human epidermal growth factor receptor-2 sheddase inhibitor for the treatment of cancer

Discovery of a potent, selective, and orally active human epidermal growth factor receptor-2 sheddase inhibitor for the treatment of cancer

  • J Med Chem. 2007 Feb 22;50(4):603-6. doi: 10.1021/jm061344o.
Wenqing Yao 1,  Jincong Zhuo,  David M Burns,  Meizhong Xu,  Colin Zhang,  Yun-Long Li,  Ding-Quan Qian,  Chunhong He,  Lingkai Weng,  Eric Shi,  Qiyan Lin,  Costas Agrios,  Timothy C Burn,  Eian Caulder,  Maryanne B Covington,  Jordan S Fridman,  Steven Friedman,  Kamna Katiyar,  Gregory Hollis,  Yanlong Li,  Changnian Liu,  Xiangdong Liu,  Cindy A Marando,  Robert Newton,  Max Pan,  Peggy Scherle,  Nancy Taylor,  Kris Vaddi,  Zelda R Wasserman,  Richard Wynn,  Swamy Yeleswaram,  Ravi Jalluri,  Michael Bower,  Bing-Bing Zhou,  Brian Metcalf
Affiliations

Affiliation

  • 1 Incyte Corporation, Experimental Station, Wilmington, Delaware 19880, USA. wyao@incyte.com
PMID: 17256836 DOI: 10.1021/jm061344o
Abstract

The design, synthesis, evaluation, and identification of a novel class of (6S,7S)-N-hydroxy-6-carboxamide-5-azaspiro[2.5]octane-7-carboxamides as the first potent and selective inhibitors of human epidermal growth factor receptor-2 (HER-2) sheddase is described. Several compounds were identified that possess excellent pharmacodynamic and pharmacokinetic properties and were shown to decrease tumor size, cleaved HER-2 extracellular domain plasma levels, and potentiate the effects of the humanized anti-HER-2 monoclonal antibody (trastuzumab) in vivo in a HER-2 overexpressing Cancer murine xenograft model.

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