Discovery of a potent, selective, and orally active human epidermal growth factor receptor-2 sheddase inhibitor for the treatment of cancer.
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.
Yao
Wenqing
W
Incyte Corporation, Experimental Station, Wilmington, Delaware 19880, USA. wyao@incyte.com
Zhuo
Jincong
J
Burns
David M
DM
Xu
Meizhong
M
Zhang
Colin
C
Li
Yun-Long
YL
Qian
Ding-Quan
DQ
He
Chunhong
C
Weng
Lingkai
L
Shi
Eric
E
Lin
Qiyan
Q
Agrios
Costas
C
Burn
Timothy C
TC
Caulder
Eian
E
Covington
Maryanne B
MB
Fridman
Jordan S
JS
Friedman
Steven
S
Katiyar
Kamna
K
Hollis
Gregory
G
Li
Yanlong
Y
Liu
Changnian
C
Liu
Xiangdong
X
Marando
Cindy A
CA
Newton
Robert
R
Pan
Max
M
Scherle
Peggy
P
Taylor
Nancy
N
Vaddi
Kris
K
Wasserman
Zelda R
ZR
Wynn
Richard
R
Yeleswaram
Swamy
S
Jalluri
Ravi
R
Bower
Michael
M
Zhou
Bing-Bing
BB
Metcalf
Brian
B
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
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