title: Discovery of a potent, selective, and orally active human epidermal growth factor receptor-2 sheddase inhibitor for the treatment of cancer.
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.
authors.affiliation: Incyte Corporation, Experimental Station, Wilmington, Delaware 19880, USA. wyao@incyte.com
authors.forename: Wenqing
authors.initials: W
authors.lastname: Yao
authors.forename: Jincong
authors.initials: J
authors.lastname: Zhuo
authors.forename: David M
authors.initials: DM
authors.lastname: Burns
authors.forename: Meizhong
authors.initials: M
authors.lastname: Xu
authors.forename: Colin
authors.initials: C
authors.lastname: Zhang
authors.forename: Yun-Long
authors.initials: YL
authors.lastname: Li
authors.forename: Ding-Quan
authors.initials: DQ
authors.lastname: Qian
authors.forename: Chunhong
authors.initials: C
authors.lastname: He
authors.forename: Lingkai
authors.initials: L
authors.lastname: Weng
authors.forename: Eric
authors.initials: E
authors.lastname: Shi
authors.forename: Qiyan
authors.initials: Q
authors.lastname: Lin
authors.forename: Costas
authors.initials: C
authors.lastname: Agrios
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Burn
authors.forename: Eian
authors.initials: E
authors.lastname: Caulder
authors.forename: Maryanne B
authors.initials: MB
authors.lastname: Covington
authors.forename: Jordan S
authors.initials: JS
authors.lastname: Fridman
authors.forename: Steven
authors.initials: S
authors.lastname: Friedman
authors.forename: Kamna
authors.initials: K
authors.lastname: Katiyar
authors.forename: Gregory
authors.initials: G
authors.lastname: Hollis
authors.forename: Yanlong
authors.initials: Y
authors.lastname: Li
authors.forename: Changnian
authors.initials: C
authors.lastname: Liu
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Liu
authors.forename: Cindy A
authors.initials: CA
authors.lastname: Marando
authors.forename: Robert
authors.initials: R
authors.lastname: Newton
authors.forename: Max
authors.initials: M
authors.lastname: Pan
authors.forename: Peggy
authors.initials: P
authors.lastname: Scherle
authors.forename: Nancy
authors.initials: N
authors.lastname: Taylor
authors.forename: Kris
authors.initials: K
authors.lastname: Vaddi
authors.forename: Zelda R
authors.initials: ZR
authors.lastname: Wasserman
authors.forename: Richard
authors.initials: R
authors.lastname: Wynn
authors.forename: Swamy
authors.initials: S
authors.lastname: Yeleswaram
authors.forename: Ravi
authors.initials: R
authors.lastname: Jalluri
authors.forename: Michael
authors.initials: M
authors.lastname: Bower
authors.forename: Bing-Bing
authors.initials: BB
authors.lastname: Zhou
authors.forename: Brian
authors.initials: B
authors.lastname: Metcalf
mesh_terms: D000284:Administration, Oral; D000577:Amides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051379:Mice; D008968:Molecular Conformation; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous; D000068878:Trastuzumab
chemical_list: D000577:Amides; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D006877:Hydroxamic Acids; D010880:Piperidines; D018719:Erb-b2 Receptor Tyrosine Kinases; D013141:Spiro Compounds; D000068878:Trastuzumab; C513090:INCB3619