CP-724714, a novel erbB2 receptor tyrosine kinase inhibitor for cancer therapy

4637 The erbB2 (neu/HER2) proto-oncogene is over-expressed in various tumor types such as carcinomas of breast, ovary, and stomach. Herceptin, an erbB2 targeted humanized monoclonal antibody produces an increase in survival for patients with breast cancers that overexpress erbB2, and has been approved by the FDA for that indication. CP-724,714 was identified as a potent and selective inhibitor of the erbB2 RTK (IC50 3.8 ng/ml). CP-724714 inhibits erbB2 receptor autophosphorylation in NIH 3T3 cells expressing a chimeric receptor consisting of the EGFR extracellular domain and the erbB2 intracellular domain (IC50 15 ng/ml) and in vitro growth of SKBr3 cells (IC50 25 ng/ml). It inhibits erbB2 autophosphorylation in vivo (ED50 ∼ 19 mg/kg, EC50 ∼ 980 ng/ml), after PO administration to athymic mice bearing FRE erbB2 tumors (Fisher rat embryonic fibroblasts transformed by activated erbB2). Oral administration (QD or BID) of CP-724714 inhibits the growth of FRE erbB2 tumors and human tumor xenografts in athymic female mice. The combination of CP-724,714 and Herceptin provided better anti-tumor efficacy than treatment by either agent alone in the BT-474 human breast carcinoma model. CP-724714 is an orally bio-available, well-tolerated compound that has progressed into clinical development.