title: Irreversible inhibition of epidermal growth factor receptor activity by 3-aminopropanamides.
abstract: Irreversible epidermal growth factor receptor (EGFR) inhibitors contain a reactive warhead which covalently interacts with a conserved cysteine residue in the kinase domain. The acrylamide fragment, a commonly employed warhead, effectively alkylates Cys797 of EGFR, but its reactivity can cause rapid metabolic deactivation or nonspecific reactions with off-targets. We describe here a new series of irreversible inhibitors containing a 3-aminopropanamide linked in position 6 to 4-anilinoquinazoline or 4-anilinoquinoline-3-carbonitrile driving portions. Some of these compounds proved to be as efficient as their acrylamide analogues in inhibiting EGFR-TK (TK = tyrosine kinase) autophosphorylation in A549 lung cancer cells. Moreover, several 3-aminopropanamides suppressed proliferation of gefitinib-resistant H1975 cells, harboring the T790M mutation in EGFR, at significantly lower concentrations than did gefitinib. A prototypical compound, N-(4-(3-bromoanilino)quinazolin-6-yl)-3-(dimethylamino)propanamide (5), did not show covalent binding to cell-free EGFR-TK in a fluorescence assay, while it underwent selective activation in the intracellular environment, releasing an acrylamide derivative which can react with thiol groups.
authors.affiliation: Dipartimento Farmaceutico, Università degli Studi di Parma, V.le G.P. Usberti 27/A, I-43124 Parma, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Carmi
authors.forename: Elena
authors.initials: E
authors.lastname: Galvani
authors.forename: Federica
authors.initials: F
authors.lastname: Vacondio
authors.forename: Silvia
authors.initials: S
authors.lastname: Rivara
authors.forename: Alessio
authors.initials: A
authors.lastname: Lodola
authors.forename: Simonetta
authors.initials: S
authors.lastname: Russo
authors.forename: Stefania
authors.initials: S
authors.lastname: Aiello
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Bordi
authors.forename: Gabriele
authors.initials: G
authors.lastname: Costantino
authors.forename: Andrea
authors.initials: A
authors.lastname: Cavazzoni
authors.forename: Roberta R
authors.initials: RR
authors.lastname: Alfieri
authors.forename: Andrea
authors.initials: A
authors.lastname: Ardizzoni
authors.forename: Pier Giorgio
authors.initials: PG
authors.lastname: Petronini
authors.forename: Marco
authors.initials: M
authors.lastname: Mor
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000814:Aniline Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006801:Humans; D010766:Phosphorylation; D011422:Propionates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D000814:Aniline Compounds; D000970:Antineoplastic Agents; D011422:Propionates; D011799:Quinazolines; D011804:Quinolines; D066246:ErbB Receptors