BIBX1382BS, but not AG1478 or PD153035, inhibits the ErbB kinases at different concentrations in intact cells

The activation of ErbB tyrosine kinase receptors (ErbB1, -2, -3, and -4) by ligand-induced homo- or heterodimerization regulates cell growth, death, a nd differentiation. AG1478 and PD153035 (also know as AG1517) have been ado pted 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 displaye d any specificity for ErbB1-mediated signaling induced by transforming grow th factor alpha (TGF-alpha) as compared to signaling initiated through the other ErbB kinases. In contrast, BIBX1382BS was more potent at inhibiting s ignaling induced by TGF-alpha than that induced by neuregulin1-beta1 or ant i-ErbB2 agonist antibodies. Interestingly, this compound blocked antibody-i nduced ErbB4 homodimer activation at even lower concentrations than ErbB1-t riggered signaling. Thus, BIBX1382BS, but not AG1478 and PD153035, can be e mployed to differentiate between the ErbB kinases in intact cells when used at appropriate concentrations. (C) 2001 Academic Press.