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
  • 1. Incyte Corporation, Experimental Station, Wilmington, Delaware 19880, USA. [email protected]
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.