Antitumor activity and pharmacokinetic properties of PF-00299804, a second-generation irreversible pan-erbB receptor tyrosine kinase inhibitor.

Abstract

Signaling through the erbB receptor family of tyrosine kinases contributes to the proliferation, differentiation, migration, and survival of a variety of cell types. Abnormalities in members of this receptor family have been shown to play a role in oncogenesis, thus making them attractive targets for anticancer treatments. PF-00299804 is a second-generation irreversible pan-erbB receptor tyrosine kinase inhibitor currently in phase I clinical trials. PF-00299804 is believed to irreversibly inhibit erbB tyrosine kinase activity through binding at the ATP site and covalent modification of nucleophilic cysteine residues in the catalytic domains of erbB family members. Oral administration of PF-00299804 causes significant antitumor activity, including marked tumor regressions in a variety of human tumor xenograft models that express and/or overexpress erbB family members or contain the double mutation (L858R/T790M) in erbB1 (EGFR) associated with resistance to gefitinib and erlotinib. Furthermore, PF-00299804 shows exceptional distribution to human tumor xenografts and excellent pharmacokinetic properties across species.

• Authors: Andrea J Gonzales, Kenneth E Hook, Irene W Althaus, Paul A Ellis, Erin Trachet, Amy M Delaney, Patricia J Harvey, Teresa A Ellis, Danielle M Amato, James M Nelson, David W Fry, Tong Zhu, Cho-Ming Loi, Stephen A Fakhoury, Kevin M Schlosser, Karen E Sexton, R Thomas Winters, Jessica E Reed, Alex J Bridges, Daniel J Lettiere, Deborah A Baker, Jianxin Yang, Helen T Lee, Haile Tecle, Patrick W Vincent
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 7 Issue 7 Pg. 1880-9 (Jul 2008) ISSN: 1535-7163 [Print] United States
• PMID: 18606718 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Quinazolinones
• dacomitinib
• ErbB Receptors
• Receptor Protein-Tyrosine Kinases

Topics

• Amino Acid Substitution
• Animals
• Antineoplastic Agents (pharmacokinetics, pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• ErbB Receptors (metabolism)
• Female
• Humans
• Mice
• Mice, SCID
• Mutation (genetics)
• Phosphorylation (drug effects)
• Quinazolinones (pharmacokinetics, pharmacology)
• Receptor Protein-Tyrosine Kinases (antagonists & inhibitors)
• Species Specificity
• Xenograft Model Antitumor Assays