Antitumor activity and pharmacokinetic properties of PF-00299804, a second-generation irreversible pan-erbB receptor tyrosine kinase inhibitor.
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.
Gonzales
Andrea J
AJ
Cancer Biology, Pfizer Global Research and Development, Ann Arbor, Michigan, USA. Andrea.Gonzales@pfizer.com
Hook
Kenneth E
KE
Althaus
Irene W
IW
Ellis
Paul A
PA
Trachet
Erin
E
Delaney
Amy M
AM
Harvey
Patricia J
PJ
Ellis
Teresa A
TA
Amato
Danielle M
DM
Nelson
James M
JM
Fry
David W
DW
Zhu
Tong
T
Loi
Cho-Ming
CM
Fakhoury
Stephen A
SA
Schlosser
Kevin M
KM
Sexton
Karen E
KE
Winters
R Thomas
RT
Reed
Jessica E
JE
Bridges
Alex J
AJ
Lettiere
Daniel J
DJ
Baker
Deborah A
DA
Yang
Jianxin
J
Lee
Helen T
HT
Tecle
Haile
H
Vincent
Patrick W
PW
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
D000970:Antineoplastic Agents; D052999:Quinazolinones; C525726:dacomitinib; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases