title: [(Alkylamino)methyl]acrylophenones: potent and selective inhibitors of the epidermal growth factor receptor protein tyrosine kinase.
abstract: [(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.
authors.affiliation: Cancer and Infectious Disease Research Department, CIBA Limited, Basel, Switzerland.
authors.forename: P
authors.initials: P
authors.lastname: Traxler
authors.forename: U
authors.initials: U
authors.lastname: Trinks
authors.forename: E
authors.initials: E
authors.lastname: Buchdunger
authors.forename: H
authors.initials: H
authors.lastname: Mett
authors.forename: T
authors.initials: T
authors.lastname: Meyer
authors.forename: M
authors.initials: M
authors.lastname: Müller
authors.forename: U
authors.initials: U
authors.lastname: Regenass
authors.forename: J
authors.initials: J
authors.lastname: Rösel
authors.forename: N
authors.initials: N
authors.lastname: Lydon
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006801:Humans; D007659:Ketones / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010766:Phosphorylation; D013329:Structure-Activity Relationship; D014443:Tyrosine / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D007659:Ketones; D014443:Tyrosine; D004815:Epidermal Growth Factor; D066246:ErbB Receptors