Structure-Based Design of erbB-2 Selective Small Molecule Kinase Inhibitors

ErbB-2 is overexpressed in 25-30 of breast cancers and is a promising therapeutic target with clinically proven outcome for the treatment of breast cancer. In breast cancers with erbB-2 overexpression, abnormal cell proliferation is caused by the extremely high tyrosine kinase activity of erbB-2. Hence, inhibition of the erbB-2 kinase activity is a promising strategy for the treatment of breast cancer. Through a powerful computerized structure-based 3D-database searching, we have discovered several potent and selective small molecule kinase inhibitors of erbB-2. One such promising lead compound potently inhibits the kinase activity of erbB-2 both in vitro and in vivo, while it has little effect on the kinase activity of EGFR, displaying an excellent selectivity between Her-2 and EGFR. Furthermore, this lead compound was shown to effectively inhibit tumor growth in multiple human breast cancer xenograft models with high Her-2 overexpression and have little effect on tumor growth in xenograft models with high level of EGFR but low level of Her-2. Our studies demonstrate that potent and selective erbB-2 kinase inhibitors may have a great therapeutic potential as a novel and molecularly targeted therapy, either alone or in combination with other therapies, for the treatment of breast cancer.