Tricyclic azepine derivatives: pyrimido[4,5-b]-1,4-benzoxazepines as a novel class of epidermal growth factor receptor kinase inhibitors.
A novel class of pyrimido[4,5-b]-1,4-benzoxazepines is described as inhibitors of epidermal growth factor receptor (EGFR) tyrosine kinase. Two compounds display potent EGFR inhibitory activity of less than 1 microM in cellular phosphorylation assays (IC(50) 0.47-0.69 microM) and are highly selective against a small kinase panel. Such compounds demonstrate anti-EGFR activity within a class that is different from any known EGFR inhibitor scaffolds. They also provide a basis for the design of kinase inhibitors with the desired selectivity profile.
Smith
Leon
L
Department of Chemistry, ImClone Systems, 180 Varick Street, New York, NY 10014, USA.
Piatnitski
Evgueni L
EL
Kiselyov
Alexander S
AS
Ouyang
Xiaohu
X
Chen
Xiaoling
X
Burdzovic-Wizemann
Sabina
S
Xu
Yongjiang
Y
Pan
Weitao
W
Chen
Xin
X
Wang
Ying
Y
Rosler
Robin L
RL
Patel
Sheetal N
SN
Chiang
Hui-Hsien
HH
Milligan
Daniel L
DL
Columbus
John
J
Wong
Wai C
WC
Doody
Jacqueline F
JF
Hadari
Yaron R
YR
D000255:Adenosine Triphosphate / Q000378:metabolism; D001381:Azepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006801:Humans; D015394:Molecular Structure; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D000255:Adenosine Triphosphate; D001381:Azepines; D066246:ErbB Receptors; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases