New C-5 substituted pyrrolotriazine dual inhibitors of EGFR and HER2 protein tyrosine kinases

Harold Mastalerz; Ming Chang; Ping Chen; Pierre Dextraze; Brian E Fink; Ashvinikumar Gavai; Bindu Goyal; Wen-Ching Han; Walter Johnson; David Langley; Francis Y Lee; Punit Marathe; Arvind Mathur; Simone Oppenheimer; Edward Ruediger; James Tarrant; John S Tokarski; Gregory D Vite; Dolatrai M Vyas; Henry Wong; Tai W Wong; Hongjian Zhang; Guifen Zhang

doi:10.1016/j.bmcl.2007.01.002

New C-5 substituted pyrrolotriazine dual inhibitors of EGFR and HER2 protein tyrosine kinases

Bioorg Med Chem Lett. 2007 Apr 1;17(7):2036-42. doi: 10.1016/j.bmcl.2007.01.002. Epub 2007 Jan 12.

Affiliation

¹ Department of Oncology Chemistry, 5 Research Parkway, Wallingford, CT 06492-1951, USA. harold.mastalerz@bms.com

PMID: 17270437
DOI: 10.1016/j.bmcl.2007.01.002

Abstract

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.

MeSH terms

Adenosine Triphosphate / chemistry
Animals
Caco-2 Cells
Chemistry, Pharmaceutical / methods*
Drug Design
Enzyme Inhibitors / pharmacology
ErbB Receptors / antagonists & inhibitors*
Humans
Inhibitory Concentration 50
Mice
Neoplasm Transplantation
Phosphates / chemistry
Pyrroles / chemical synthesis*
Pyrroles / pharmacology
Receptor, ErbB-2 / antagonists & inhibitors*
Ribose / chemistry
Triazines / chemical synthesis*
Triazines / pharmacology

Substances

Enzyme Inhibitors
Phosphates
Pyrroles
Triazines
Ribose
Adenosine Triphosphate
ErbB Receptors
Receptor, ErbB-2