Epidermal growth factor receptor (EGFR/ErbB-1) and Her-2 (ErbB-2), members of the Type 1 receptor tyrosine kinase family, are frequently disregulated in human epithelial tumors, via autocrine stimulation, overexpression, or mutation and play a key role in cell proliferation and differentiation. Overexpression of these receptors is found in a variety of cancers such as breast, ovarian, colon, head and neck and prostate cancers. The ErbB receptors can be activated through homo or heterodimerization with other receptors resulting in phosphorylation events and downstream signaling that produces excessive growth by inducing cell proliferation and inhibiting apoptotic pathways. In an attempt to identify most potent kinase inhibitors, we developed a library of small molecules containing a backbone of pyrimidines, quinolines, quinazolines and benzothiazinones.  While screening these compounds in cytotoxicity assay, we found that 4-aryl/benzylthio quinazolines are found to be very effective in killing EGFR+ cancer cells. The kinase profiling study of this chemotype showed that ON128030 and ON128060 are found to be selectively inhibiting EGFRK unlike Iressa� which inhibits both EGFR and ErbB2 (Her-2) receptor kinases. In this presentation, we describe the synthesis, characterization, structure activity relationship (SAR), in vitro cytotoxicity and kinase profile of the lead molecule.

Design, synthesis and biological study of novel epidermal growth factor receptor kinase (EGFRK) inhibitors

243rd National Meeting (2012)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.