Discovery and pharmacologic characterization of CP-724,714, a selective ErbB2 tyrosine kinase inhibitor.

Abstract

Amplification and overexpression of erbB2 (Her-2/neu) proto-oncogene has been linked to human malignancies including tumors of the breast, ovary, and stomach. It has been implicated in tumor growth, sensitivity to standard chemotherapy, prognosis of patients, and disease-free survival. Although the clinical use of trastuzumab (Herceptin) has prolonged the survival of breast cancer patients with erbB2-overexpressing tumors, there is an urgent need for more potent and orally bioavailable small-molecule inhibitors. CP-724,714 is a potent inhibitor of erbB2 receptor autophosphorylation in intact cells and is currently undergoing phase I clinical trials. Here, we describe the effects of CP-724,714 in vitro and in vivo in human breast cancer models. CP-724,714 is selective for inhibiting growth of HER2-driven cell lines. In addition, we show that it induces G1 cell cycle block in erbB2-overexpressing BT-474 human breast carcinoma cells and inhibits erbB2 autophosphorylation in xenografts when administered p.o. to athymic mice. It induces a marked reduction of extracellular signal-regulated kinase and Akt phosphorylation, tumor cell apoptosis, and release of caspase-3. P.o. administration (q.d. or b.i.d.) of CP-724,714 inhibits the growth of erbB2-overexpressing tumors in athymic mice without overt adverse effects.

• Authors: Jitesh P Jani, Richard S Finn, Mary Campbell, Kevin G Coleman, Richard D Connell, Nicolas Currier, Erling O Emerson, Eugenia Floyd, Shawn Harriman, John C Kath, Joel Morris, James D Moyer, Leslie R Pustilnik, Kristina Rafidi, Sherry Ralston, Ann Marie K Rossi, Stefanus J Steyn, Larry Wagner, Steven M Winter, Samit K Bhattacharya
• Journal: Cancer research (Cancer Res) Vol. 67 Issue 20 Pg. 9887-93 (Oct 15 2007) ISSN: 0008-5472 [Print] United States
• PMID: 17942920 (Publication Type: Journal Article)

Chemical References

• 2-methoxy-N-(3-(4-((3-methyl-4-((6-methyl-3-pyridinyl)oxy)phenyl)amino)-6-quinazolinyl)-2-propenyl)acetamide
• MAS1 protein, human
• Protein Kinase Inhibitors
• Proto-Oncogene Mas
• Quinazolines
• Receptor, ErbB-2
• Proto-Oncogene Proteins c-akt
• Extracellular Signal-Regulated MAP Kinases

Topics

• Animals
• Apoptosis (drug effects)
• Breast Neoplasms (drug therapy, metabolism, pathology)
• Cell Cycle (drug effects)
• Cell Growth Processes (drug effects)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Female
• Humans
• Mice
• Mice, Nude
• NIH 3T3 Cells
• Phosphorylation (drug effects)
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Mas
• Proto-Oncogene Proteins c-akt (metabolism)
• Quinazolines (pharmacology)
• Receptor, ErbB-2 (antagonists & inhibitors, metabolism)
• Xenograft Model Antitumor Assays