[(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.
Traxler
P
P
Cancer and Infectious Disease Research Department, CIBA Limited, Basel, Switzerland.
Trinks
U
U
Buchdunger
E
E
Mett
H
H
Meyer
T
T
Müller
M
M
Regenass
U
U
Rösel
J
J
Lydon
N
N
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
D000970:Antineoplastic Agents; D007659:Ketones; D014443:Tyrosine; D004815:Epidermal Growth Factor; D066246:ErbB Receptors