title: Structure-activity relationships in a series of 5-[(2,5-dihydroxybenzyl)amino]salicylate inhibitors of EGF-receptor-associated tyrosine kinase: importance of additional hydrophobic aromatic interactions.
abstract: Potent inhibitors of EGF-dependent protein tyrosine kinase (PTK) activity were synthesized in a series of 5-[(2,5-dihydroxybenzyl)amino]salicylates. Several of these compounds inhibited EGF-dependent DNA synthesis in ER 22 cells with IC50 < 1 microM. In this series of PTK inhibitors, the role of the salicylate moiety as a potential divalent ion chelator was tested and found to be nonessential in all cases. The length and ramification of the substituting carboxyl group were investigated to improve cellular bioavailability, and this analysis provided compounds with increased inhibitory effect on EGF-induced DNA synthesis. Salicylates esterified with long hydrophobic chains were shown to be noncompetitive inhibitors of ATP, in contrast to the free acid and methyl salicylate. Moreover, all the tested inhibitors were shown to be noncompetitive inhibitors of the peptide substrate. Structure-activity relationships allowed us to suspect a hydrophobic pocket in the tyrosine kinase domain, preferentially interacting with aromatic rings. Finally, the selectivity of the best inhibitors was tested against other kinases, and they were found to be selective for tyrosine kinase. They were also shown to be good inhibitors of EGF-receptor autophosphorylation.
authors.affiliation: Département de Pharmacochimie Moléculaire et Structurale, U266 INSERM-URA D1500 CNRS, Faculté de Pharmacie, Paris, France.
authors.forename: H
authors.initials: H
authors.lastname: Chen
authors.forename: J
authors.initials: J
authors.lastname: Boiziau
authors.forename: F
authors.initials: F
authors.lastname: Parker
authors.forename: P
authors.initials: P
authors.lastname: Mailliet
authors.forename: A
authors.initials: A
authors.lastname: Commerçon
authors.forename: B
authors.initials: B
authors.lastname: Tocque
authors.forename: J B
authors.initials: JB
authors.lastname: Le Pecq
authors.forename: B P
authors.initials: BP
authors.lastname: Roques
authors.forename: C
authors.initials: C
authors.lastname: Garbay
mesh_terms: D000818:Animals; D001593:Benzyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D066246:ErbB Receptors / Q000187:drug effects*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats; D012459:Salicylates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D001593:Benzyl Compounds; D012459:Salicylates; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases