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 ph...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2007-04, Vol.17 (7), p.2036-2042
Hauptverfasser:	Mastalerz, Harold, Chang, Ming, Chen, Ping, Dextraze, Pierre, Fink, Brian E., Gavai, Ashvinikumar, Goyal, Bindu, Han, Wen-Ching, Johnson, Walter, Langley, David, Lee, Francis Y., Marathe, Punit, Mathur, Arvind, Oppenheimer, Simone, Ruediger, Edward, Tarrant, James, Tokarski, John S., Vite, Gregory D., Vyas, Dolatrai M., Wong, Henry, Wong, Tai W., Zhang, Hongjian, Zhang, Guifen
Format:	Artikel
Sprache:	eng
Schlagworte:	Adenosine Triphosphate - chemistry Animals Antineoplastic agents Biological and medical sciences Caco-2 Cells Chemistry, Pharmaceutical - methods Drug Design EGFR Enzyme Inhibitors - pharmacology General aspects HER2 Humans Inhibitory Concentration 50 Medical sciences Mice Neoplasm Transplantation Pharmacology. Drug treatments Phosphates - chemistry Pyrroles - chemical synthesis Pyrroles - pharmacology Pyrrolotriazine Receptor tyrosine kinase inhibitor Receptor, Epidermal Growth Factor - antagonists & inhibitors Receptor, ErbB-2 - antagonists & inhibitors Ribose - chemistry Triazines - chemical synthesis Triazines - pharmacology
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Beschreibung
Zusammenfassung:	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. 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.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2007.01.002