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

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.

Citation

Caterina Carmi, Elena Galvani, Federica Vacondio, Silvia Rivara, Alessio Lodola, Simonetta Russo, Stefania Aiello, Fabrizio Bordi, Gabriele Costantino, Andrea Cavazzoni, Roberta R Alfieri, Andrea Ardizzoni, Pier Giorgio Petronini, Marco Mor. Irreversible inhibition of epidermal growth factor receptor activity by 3-aminopropanamides. Journal of medicinal chemistry. 2012 Mar 8;55(5):2251-64

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PMID: 22280453

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