New C-5 substituted pyrrolotriazine dual inhibitors of EGFR and HER2 protein tyrosine kinases.
Novel C-5 substituted pyrrolotriazines were optimized for dual EGFR and HER2 protein tyrosine kinase inhibition. The lead compound exhibited promising oral efficacy in both EGFR and HER2 driven human tumor xenograft models. It is hypothesized that its C-5 morpholine side chain binds in the ribose phosphate portion of the ATP binding pocket.
Mastalerz
Harold
H
Department of Oncology Chemistry, 5 Research Parkway, Wallingford, CT 06492-1951, USA. harold.mastalerz@bms.com
Chang
Ming
M
Chen
Ping
P
Dextraze
Pierre
P
Fink
Brian E
BE
Gavai
Ashvinikumar
A
Goyal
Bindu
B
Han
Wen-Ching
WC
Johnson
Walter
W
Langley
David
D
Lee
Francis Y
FY
Marathe
Punit
P
Mathur
Arvind
A
Oppenheimer
Simone
S
Ruediger
Edward
E
Tarrant
James
J
Tokarski
John S
JS
Vite
Gregory D
GD
Vyas
Dolatrai M
DM
Wong
Henry
H
Wong
Tai W
TW
Zhang
Hongjian
H
Zhang
Guifen
G
D000255:Adenosine Triphosphate / Q000737:chemistry; D000818:Animals; D018938:Caco-2 Cells; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D009368:Neoplasm Transplantation; D010710:Phosphates / Q000737:chemistry; D011758:Pyrroles / Q000138:chemical synthesis* / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D012266:Ribose / Q000737:chemistry; D014227:Triazines / Q000138:chemical synthesis* / Q000494:pharmacology
D000255:Adenosine Triphosphate; D004791:Enzyme Inhibitors; D066246:ErbB Receptors; D010710:Phosphates; D011758:Pyrroles; D018719:Erb-b2 Receptor Tyrosine Kinases; D012266:Ribose; D014227:Triazines