Discovery of EGFR selective 4,6-disubstituted pyrimidines from a combinatorial kinase-directed heterocycle library.
The epidermal growth factor receptor (EGFR) tyrosine kinase was one of the first receptor tyrosine kinases to be targeted for drug development by the pharmaceutical industry due to its ubiquitous overexpression in a variety of tumors. Despite the validation of several quinazoline-based scaffolds in the clinic, there is a dearth of alternative chemical structure classes that are capable of inhibiting EGFR kinase activity selectively. Here we describe the discovery of potent and highly selective 4,6-disubstituted pyrimidine inhibitors of enzymatic and cellular EGFR activity and provide an explanation for their exceptional degree of kinase selectivity.
Departments of Chemistry and Cell Biology, Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA.
Qiong
Q
Zhang
Yi
Y
Liu
Feng
F
Gao
Qiang
Q
Ding
Charles
C
Cho
Wooyoung
W
Hur
Yunho
Y
Jin
Tetsuo
T
Uno
Claudio A P
CA
Joazeiro
Nathanael
N
Gray
D020650:Combinatorial Chemistry Techniques / Q000379:methods; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D000077156:Gefitinib; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D011743:Pyrimidines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D011799:Quinazolines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship
D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011799:Quinazolines; D066246:ErbB Receptors; D000077156:Gefitinib