[(Alkylamino)methyl]acrylophenones: potent and selective inhibitors of the epidermal growth factor receptor protein tyrosine kinase.

[(Alkylamino)methyl]acrylophenones and (alkylamino)propiophenones, bearing a spacer moiety such as the benzyloxy or (benzoylsulfonyl)oxy group in the 4-position, represent a novel class of inhibitors of the epidermal growth factor (EGF) receptor protein tyrosine kinase with a high degree of selectivity versus other tyrosine and serine/threonine kinases. The most active compounds inhibited the EGF receptor protein tyrosine kinase from A431 cell membranes with IC50 values of < 0.5 microM. Derivatives with a benzyloxy substituent in the 4-position of the aromatic ring inhibited both the EGF receptor kinase and the proliferation of an EGF-dependent mouse epidermal keratinocyte cell line (BALB/MK) but were only marginally active in the inhibition of the cellular EGF-dependent tyrosine phosphorylation. Compound 18 inhibited ligand-induced tyrosine phosphorylation and BALB/MK cell proliferation with IC50 values of approximately 100 and 1.21 microM, respectively, and showed antitumor activity in vivo in a nude mouse model. However, the discrepancy between the IC50 values for antiproliferative activity and cellular tyrosine phosphorylation as well as the relatively low tolerability in animals suggests a second site of action of this class of inhibitors. Nevertheless, [(alkylamino)methyl]acrylophenones and (alkylamino)propiophenones may prove to be interesting tools for studying the action of tyrosine kinases.