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.

Irreversible Inhibition of Epidermal Growth Factor Receptor Activity by 3-Aminopropanamides / Carmi, Caterina; Galvani, Elena; Vacondio, Federica; Rivara, Silvia; Lodola, Alessio; Russo, Simonetta; Bordi, Fabrizio; Costantino, Gianluca; Cavazzoni, Andrea; Alfieri, Roberta; Ardizzoni, A.; Petronini, P. G.; Mor, Marco; Costantino, Gabriele. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 1520-4804. - 55:(2012), pp. 2251-2264. [10.1021/jm201507x]

Irreversible Inhibition of Epidermal Growth Factor Receptor Activity by 3-Aminopropanamides.

CARMI, Caterina;GALVANI, Elena;VACONDIO, Federica;RIVARA, Silvia;LODOLA, Alessio;RUSSO, Simonetta;BORDI, Fabrizio;COSTANTINO, Gianluca;CAVAZZONI, Andrea;ALFIERI, Roberta;Petronini, P. G.;MOR, Marco;COSTANTINO, Gabriele
2012-01-01

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.
2012
Irreversible Inhibition of Epidermal Growth Factor Receptor Activity by 3-Aminopropanamides / Carmi, Caterina; Galvani, Elena; Vacondio, Federica; Rivara, Silvia; Lodola, Alessio; Russo, Simonetta; Bordi, Fabrizio; Costantino, Gianluca; Cavazzoni, Andrea; Alfieri, Roberta; Ardizzoni, A.; Petronini, P. G.; Mor, Marco; Costantino, Gabriele. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 1520-4804. - 55:(2012), pp. 2251-2264. [10.1021/jm201507x]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11381/2395144
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