The erbB family of receptor tyrosine kinases is implicated in human cancer. Specifically EGFR and HER2 overexpression, mutation or amplification can be associated with poor prognosis and cause many types of cancer including breast, gastric, head and neck, and non-small lung cell cancer. We have developed a series of novel non-quinazoline small molecule pan-erbB inhibitors that have low nanomolar potency against erbB1,2 and 4. They inhibit EGF-induced phosphorylation of EGFR in A431 cells, the constitutive phosphorylation of HER2 in the HER2-overexpressing cell line SKBR-3, and the proliferation of HER2- and EGFR-overexpressing cells in tissue culture. Most importantly, they potently inhibit the growth of the HER2-overexpressing N87 gastric carcinoma tumor xenografts, the HER2-overexpressing BT474 breast carcinoma tumor xenograft and the EGFR-overexpressing A431 epidermoid carcinoma tumor xenograft when administered orally in nude mice. Compounds in this series also inhibit Bruton’s tyrosine kinase (BTK), ETK and BRK potently, differentiating them from other erbB inhibitors. The activity and pharmacological properties of these compounds make them excellent candidates for clinical development. The biological characterization of lead compounds in this series will be described.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]