Discovery and biological evaluation of potent dual ErbB-2/EGFR tyrosine kinase inhibitors: 6-thiazolylquinazolines.
We have identified a novel class of 6-thiazolylquinazolines as potent and selective inhibitors of both ErbB-2 and EGFR tyrosine kinase activity, with IC(50) values in the nanomolar range. These compounds inhibited the growth of both EGFR (HN5) and ErbB-2 (BT474) over-expressing human tumor cell lines in vitro. Using xenograft models of the same cell lines, we found that the compounds given orally inhibited in vivo tumor growth significantly compared with control animals.
Gaul
Micheal D
MD
GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, USA.
Guo
Yu
Y
Affleck
Karen
K
Cockerill
G Stuart
GS
Gilmer
Tona M
TM
Griffin
Robert J
RJ
Guntrip
Stephen
S
Keith
Barry R
BR
Knight
Wilson B
WB
Mullin
Robert J
RJ
Murray
Doris M
DM
Rusnak
David W
DW
Smith
Kathryn
K
Tadepalli
Sarva
S
Wood
Edgar R
ER
Lackey
Karen
K
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008815:Mice, Inbred Strains; D009374:Neoplasms, Experimental / Q000188:drug therapy; D011799:Quinazolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics* / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D066246:ErbB Receptors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases