Discovery and development of CP-724714, a selective HER2 receptor tyrosine kinase inhibitor

Abstract

3122 Background: The HER2 (neu/erbB2) proto-oncogene has been linked to human malignancies including tumors of the breast, ovary and stomach. Amplification of the HER2 gene and over-expression of this membrane receptor tyrosine kinase has been implicated in tumor growth, sensitivity to standard chemotherapy, prognosis of patients and disease free survival. Methods: Novel compounds were evaluated as inhibitors of recombinant HER2 tyrosine kinase-catalyzed phosphorylation of poly-glu/tyr and of the EGF-induced autophosphorylation of cellular epidermal growth factor receptor or a chimeric protein consisting of the EGFR extracellular domain/HER2 intracellular domain. The title inhibitor was further evaluated for its ability to reduce HER2 phosphorylation and growth in human tumor xenografts of athymic mice. Results: CP-724,714, a potent, orally active HER2 inhibitor, was identified and characterized for further development. This compound inhibits HER2 kinase (IC50 3.8 ng/ml) and is selective for HER2 vs. HER1, HER4 and other tyrosine kinases examined. CP-724714 reduces EGF-induced HER2 receptor phosphorylation in NIH 3T3 cells expressing a chimeric receptor consisting of the EGFR extracellular domain and the HER2 intracellular domain (IC50 15 ng/ml) and the growth of SKBr3 cells (IC50 25 ng/ml). Pre-clinical findings suggest that CP-724,714 is an orally bio-available compound with moderate clearance (11–12 ml/min/kg), and a low probability of drug:drug interactions. It reduces HER2 autophosphorylation of tumors in vivo (ED50 ∼ 19 mg/kg, EC50 ∼ 980 ng/ml), after oral administration to athymic mice bearing FRE erbB2 tumors (Fisher rat embryonic fibroblasts over-expressing HER2), and inhibited the growth of these tumors as well as human tumor xenografts. In nonclinical toxicology studies up to 1-month in duration, CP-724,714 was relatively well-tolerated in both Sprague-Dawley rats and Beagle dogs. Conclusions: CP-724714 is a novel HER2 inhibitor now in Phase I clinical trials. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Pfizer