title: BIBX1382BS, but not AG1478 or PD153035, inhibits the ErbB kinases at different concentrations in intact cells.
abstract: The activation of ErbB tyrosine kinase receptors (ErbB1, -2, -3, and -4) by ligand-induced homo- or heterodimerization regulates cell growth, death, and differentiation. AG1478 and PD153035 (also know as AG1517) have been adopted as specific ErbB1 inhibitors based on their high specificity for ErbB1 as compared to ErbB2 in in vitro kinase assays. We compared their ability to inhibit ErbB receptor signaling in intact cells to that of a novel ErbB receptor kinase inhibitor, BIBX1382BS. Neither AG1478 nor PD153035 displayed any specificity for ErbB1-mediated signaling induced by transforming growth factor alpha (TGF-alpha) as compared to signaling initiated through the other ErbB kinases. In contrast, BIBX1382BS was more potent at inhibiting signaling induced by TGF-alpha than that induced by neuregulin1-beta1 or anti-ErbB2 agonist antibodies. Interestingly, this compound blocked antibody-induced ErbB4 homodimer activation at even lower concentrations than ErbB1-triggered signaling. Thus, BIBX1382BS, but not AG1478 and PD153035, can be employed to differentiate between the ErbB kinases in intact cells when used at appropriate concentrations.
authors.affiliation: Apoptosis Laboratory, Institute of Cancer Biology, Danish Cancer Society, Copenhagen, Denmark.
authors.forename: M
authors.initials: M
authors.lastname: Egeblad
authors.forename: O H
authors.initials: OH
authors.lastname: Mortensen
authors.forename: L C
authors.initials: LC
authors.lastname: van Kempen
authors.forename: M
authors.initials: M
authors.lastname: Jäättelä
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006801:Humans; D015151:Immunoblotting; D008024:Ligands; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D020890:Neuregulin-1 / Q000378:metabolism; D009930:Organic Chemicals; D010766:Phosphorylation; D011799:Quinazolines / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors; D066247:Receptor, ErbB-4; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D016211:Transforming Growth Factor alpha / Q000378:metabolism; D014407:Tumor Cells, Cultured; D020032:Tyrphostins / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D066246:ErbB Receptors; D008024:Ligands; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D020890:Neuregulin-1; D009930:Organic Chemicals; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D066247:Receptor, ErbB-4; D011994:Recombinant Proteins; D016211:Transforming Growth Factor alpha; D020032:Tyrphostins; C423062:BIBX 1382BS; C117467:neuregulin beta; C101044:RTKI cpd; C587689:ERBB4 protein, human; C088860:4-((3-bromophenyl)amino)-6,7-dimethoxyquinazoline