New dual inhibitors of EGFR and HER2 protein tyrosine kinases.
A novel series of dual EGFR and HER2 inhibitors based on the pyrrolo[2,1-f][1,2,4]triazine nucleus is described. A general route toward their synthesis, which enables functionalization at multiple sites, has been developed. Biological evaluation in enzymatic and cell-based assays has identified a series of C-6 carbamates with potent biochemical and cellular activities.
Fink
Brian E
BE
Department of Oncology Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 4000, Princeton, NJ 08543-4000, USA. brian.fink@bms.com
Vite
Gregory D
GD
Mastalerz
Harold
H
Kadow
John F
JF
Kim
Soong-Hoon
SH
Leavitt
Kenneth J
KJ
Du
Karen
K
Crews
Donald
D
Mitt
Toomas
T
Wong
Tai W
TW
Hunt
John T
JT
Vyas
Dolatrai M
DM
Tokarski
John S
JS
D001665:Binding Sites; D002219:Carbamates / Q000138:chemical synthesis / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006801:Humans; D008958:Models, Molecular; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis / Q000494:pharmacology
D002219:Carbamates; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D014227:Triazines