title: 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.affiliation: Cancer Biology, Pfizer Global Research and Development, Ann Arbor, Michigan, USA. Andrea.Gonzales@pfizer.com
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: Gonzales
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Hook
authors.forename: Irene W
authors.initials: IW
authors.lastname: Althaus
authors.forename: Paul A
authors.initials: PA
authors.lastname: Ellis
authors.forename: Erin
authors.initials: E
authors.lastname: Trachet
authors.forename: Amy M
authors.initials: AM
authors.lastname: Delaney
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Harvey
authors.forename: Teresa A
authors.initials: TA
authors.lastname: Ellis
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Amato
authors.forename: James M
authors.initials: JM
authors.lastname: Nelson
authors.forename: David W
authors.initials: DW
authors.lastname: Fry
authors.forename: Tong
authors.initials: T
authors.lastname: Zhu
authors.forename: Cho-Ming
authors.initials: CM
authors.lastname: Loi
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Fakhoury
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Schlosser
authors.forename: Karen E
authors.initials: KE
authors.lastname: Sexton
authors.forename: R Thomas
authors.initials: RT
authors.lastname: Winters
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Reed
authors.forename: Alex J
authors.initials: AJ
authors.lastname: Bridges
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Lettiere
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Baker
authors.forename: Jianxin
authors.initials: J
authors.lastname: Yang
authors.forename: Helen T
authors.initials: HT
authors.lastname: Lee
authors.forename: Haile
authors.initials: H
authors.lastname: Tecle
authors.forename: Patrick W
authors.initials: PW
authors.lastname: Vincent
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D052999:Quinazolinones / Q000493:pharmacokinetics* / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013045:Species Specificity; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D052999:Quinazolinones; C525726:dacomitinib; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases