title: The characterization of novel, dual ErbB-2/EGFR, tyrosine kinase inhibitors: potential therapy for cancer.
abstract: The type I receptor tyrosine kinases constitute a family of transmembrane proteins involved in various aspects of cell growth and survival and have been implicated in the initiation and progression of several types of human malignancies. The best characterized of these proteins are the epidermal growth factor receptor (EGFR) and ErbB-2 (HER-2/neu). We have developed potent quinazoline and pyrido-[3,4-d]-pyrimidine small molecules that are dual inhibitors of ErbB-2 and EGFR. The compounds demonstrate potent in vitro inhibition of the ErbB-2 and EGFR kinase domains with IC(50)s <80 nM. Growth of ErbB-2- and EGFR-expressing tumor cell lines is inhibited at concentrations <0.5 microM. Selectivity for tumor cell growth inhibition versus normal human fibroblast growth inhibition ranges from 10- to >75-fold. Tumor growth in mouse s.c. xenograft models of the BT474 and HN5 cell lines is inhibited in a dose-responsive manner using oral doses of 10 and 30 mg/kg twice per day. In addition, the tested compounds caused a reduction of ErbB-2 and EGFR autophosphorylation in tumor fragments from these xenograft models. These data indicate that these compounds have potential use as therapy in the broad population of cancer patients overexpressing ErbB-2 and/or EGFR.
authors.affiliation: Department of Cancer Biology, GlaxoSmithKline, Research Triangle Park, North Carolina 27709, USA.
authors.forename: D W
authors.initials: DW
authors.lastname: Rusnak
authors.forename: K
authors.initials: K
authors.lastname: Affleck
authors.forename: S G
authors.initials: SG
authors.lastname: Cockerill
authors.forename: C
authors.initials: C
authors.lastname: Stubberfield
authors.forename: R
authors.initials: R
authors.lastname: Harris
authors.forename: M
authors.initials: M
authors.lastname: Page
authors.forename: K J
authors.initials: KJ
authors.lastname: Smith
authors.forename: S B
authors.initials: SB
authors.lastname: Guntrip
authors.forename: M C
authors.initials: MC
authors.lastname: Carter
authors.forename: R J
authors.initials: RJ
authors.lastname: Shaw
authors.forename: A
authors.initials: A
authors.lastname: Jowett
authors.forename: J
authors.initials: J
authors.lastname: Stables
authors.forename: P
authors.initials: P
authors.lastname: Topley
authors.forename: E R
authors.initials: ER
authors.lastname: Wood
authors.forename: P S
authors.initials: PS
authors.lastname: Brignola
authors.forename: S H
authors.initials: SH
authors.lastname: Kadwell
authors.forename: B R
authors.initials: BR
authors.lastname: Reep
authors.forename: R J
authors.initials: RJ
authors.lastname: Mullin
authors.forename: K J
authors.initials: KJ
authors.lastname: Alligood
authors.forename: B R
authors.initials: BR
authors.lastname: Keith
authors.forename: R M
authors.initials: RM
authors.lastname: Crosby
authors.forename: D M
authors.initials: DM
authors.lastname: Murray
authors.forename: W B
authors.initials: WB
authors.lastname: Knight
authors.forename: T M
authors.initials: TM
authors.lastname: Gilmer
authors.forename: K
authors.initials: K
authors.lastname: Lackey
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D011799:Quinazolines / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D066246:ErbB Receptors; D006131:Growth Inhibitors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases