A Specific Inhibitor of the Epidermal Growth Factor Receptor Tyrosine Kinase

Abstract

A small molecule called PD 153035 inhibited the epidermal growth factor (EGF) receptor tyrosine kinase with a 5-pM inhibition constant. The inhibitor was specific for the EGF receptor tyrosine kinase and inhibited other purified tyrosine kinases only at micromolar or higher concentrations. PD 153035 rapidly suppressed autophosphorylation of the EGF receptor at low nanomolar concentrations in fibroblasts or in human epidermoid carcinoma cells and selectively blocked EGF-mediated cellular processes including mitogenesis, early gene expression, and oncogenic transformation. PD 153035 demonstrates an increase in potency over that of other tyrosine kinase inhibitors of four to five orders of magnitude for inhibition of isolated EGF receptor tyrosine kinase and three to four orders of magnitude for inhibition of cellular phosphorylation.

Growth inhibition of human lung adenocarcinoma cells by antibodies against epidermal growth factor receptor and by ganglioside GM3: involvement of receptor-directed protein tyrosine phosphatase(s)

“…The specific EGFR-blocking tyrphostins, AG 1478 and AG 1517, were kindly provided by Drs Gazit and Levitzki (Jerusalem, Israel), (Fry et al, 1994;Osherov and Levitzki, 1994;Levitzki and Gazit, 1995). They were dissolved in dimethyl sulphoxide (DMSO); for application in cell culture, the final DMSO concentration in the assays was < 0.…”

Dual effect of erbB-2 depletion on the regulation of DNA repair and cell cycle mechanisms in non-small cell lung cancer cells

“…Therefore, selective modulation of erbB signaling pathways has emerged as a potential therapeutic target in cancer. Indeed, strategies to inhibit erbB receptors using antagonists (Arteaga et al, 1994;Pietras et al, 1994;Deshane et al, 1996), antisense (Vaughn et al, 1995), or synthetic inhibitors (Fry et al, 1994;Miller et al, 1994;Zhang and Hung, 1996) have proven e cacy in experimental models, and many of these approaches are currently under clinical trials. Immunological approaches using erbB-2 antagonists have shown that erbB signaling regulates a number of mechanisms that can a ect cellular response to chemotherapy, i.e.…”

EGF receptor signaling inhibits keratinocyte apoptosis: evidence for mediation by Bcl-XL

“…Thus, PD153035 displayed 20-fold higher inhibitory potency against ErbB-2 than against any of ®ve other tyrosine kinases (Fry et al, 1994). While its selectivity for ErbB-1 within the ErbB family has not been reported in detail, PD153035 was 10 6 times more potent against ErbB-1 (as a nity-puri®ed receptors from A431 cells, IC 50 =29 pM) than against ErbB-2 (as overexpressed soluble cytoplasmic domains, IC 50 =2.3 mM) (Fry et al, 1994). Nanomolar concentrations of PD153035 markedly inhibited HaCaT cell growth, with an IC 50 of less than 30 nM (Figure 1a).…”

“…(Fry et al, 1994) HaCaT is a spontaneously-immortalized, nontumorigenic keratinocyte cell line derived from normal-appearing back skin of a 62 year old male (Boukamp et al, 1988). Although this line carries mutations in both p53 alleles (Lehman et al, 1993) and displays a transformed phenotype in vitro, it is capable of extensive di erentiation upon transplantation to nude mice (Boukamp et al, 1988).…”

“…PD153035 and other low molecular weight inhibitors of ErbB tyrosine kinase activity are thought to owe their selectivity to interactions with structures in the kinase domain unique to the ErbB family (Fry et al, 1997;Hanks and Hunter, 1995). Thus, PD153035 displayed 20-fold higher inhibitory potency against ErbB-2 than against any of ®ve other tyrosine kinases (Fry et al, 1994). While its selectivity for ErbB-1 within the ErbB family has not been reported in detail, PD153035 was 10 6 times more potent against ErbB-1 (as a nity-puri®ed receptors from A431 cells, IC 50 =29 pM) than against ErbB-2 (as overexpressed soluble cytoplasmic domains, IC 50 =2.3 mM) (Fry et al, 1994).…”