Novel C-5 aminomethyl pyrrolotriazine dual inhibitors of EGFR and HER2 protein tyrosine kinases.
Novel C-5 aminomethyl pyrrolotriazines were prepared and optimized for dual EGFR and HER2 protein tyrosine kinase inhibition. The homopiperazine, 1p, emerged as a key lead and it showed promising oral efficacy in EGFR and dual EGFR/HER2 driven human tumor xenograft models. It is hypothesized that the C-5 homopiperazine side chain binds in the ribose-phosphate portion of the ATP binding pocket.
Mastalerz
Harold
H
Department of Oncology Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492-1951, USA. harold.mastalerz@bms.com
Chang
Ming
M
Gavai
Ashvinikumar
A
Johnson
Walter
W
Langley
David
D
Lee
Francis Y
FY
Marathe
Punit
P
Mathur
Arvind
A
Oppenheimer
Simone
S
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
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004354:Drug Screening Assays, Antitumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006801:Humans; D008744:Methylamines / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D009368:Neoplasm Transplantation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014227:Triazines / Q000737:chemistry / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D066246:ErbB Receptors; D008744:Methylamines; D011505:Protein-Tyrosine Kinases; D011758:Pyrroles; D018719:Erb-b2 Receptor Tyrosine Kinases; D014227:Triazines; C521361:aminomethyl pyrrolotriazine