Irreversible inhibition of epidermal growth factor receptor activity by 3-aminopropanamides.

Stefania Aiello, Caterina Carmi, Silvia Rivara, Elena Galvani, Simonetta Russo, Andrea Ardizzoni, Alessio Lodola, Andrea Cavazzoni, Pier Giorgio Petronini, Marco Mor, Roberta R. Alfieri, Gabriele Costantino, Fabrizio Bordi, Federica Vacondio

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50 Citazioni (Scopus)


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.
Lingua originaleEnglish
pagine (da-a)2251-2264
Numero di pagine14
RivistaJournal of Medicinal Chemistry
Stato di pubblicazionePublished - 2012

All Science Journal Classification (ASJC) codes

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