In the present study, a small set of reversible or irreversible 4-anilinoquinazoline EGFR inhibitors was tested in A549 cells at early (1 h) and late (8 h) time points after inhibitor removal from culture medium. A combination of assays was employed to explain the observed long-lasting inhibition of EGFR autophosphorylation. We found that EGFR inhibition at 8 h can be due, besides to the covalent interaction of the inhibitor with Cys797, as for PD168393 (2) and its prodrug 4, to the intracellular accumulation of non-covalent inhibitors by means of an active cell uptake, as for 5 and 6. Compounds 5-6 showed similar potency and duration of inhibition of EGFR autophosphorylation as the covalent inhibitor 2, while being devoid of reactive groups forming covalent bonds with protein thiols.

Long-lasting inhibition of EGFR autophosphorylation in A549 tumor cells by intracellular accumulation of non-covalent inhibitors / Vacondio, Federica; Carmi, Caterina; Elena, Galvani; Bassi, Michele; Silva, Claudia; Lodola, Alessio; Rivara, Silvia; Cavazzoni, Andrea; Alfieri, Roberta; Petronini, Pier Giorgio; Mor, Marco. - In: BIOORGANIC & MEDICINAL CHEMISTRY LETTERS. - ISSN 0960-894X. - 23:(2013), pp. 5290-5294. [10.1016/j.bmcl.2013.08.008]

Long-lasting inhibition of EGFR autophosphorylation in A549 tumor cells by intracellular accumulation of non-covalent inhibitors

VACONDIO, Federica;CARMI, Caterina;BASSI, Michele;SILVA, Claudia;LODOLA, Alessio;RIVARA, Silvia;CAVAZZONI, Andrea;ALFIERI, Roberta;PETRONINI, Pier Giorgio;MOR, Marco
2013

Abstract

In the present study, a small set of reversible or irreversible 4-anilinoquinazoline EGFR inhibitors was tested in A549 cells at early (1 h) and late (8 h) time points after inhibitor removal from culture medium. A combination of assays was employed to explain the observed long-lasting inhibition of EGFR autophosphorylation. We found that EGFR inhibition at 8 h can be due, besides to the covalent interaction of the inhibitor with Cys797, as for PD168393 (2) and its prodrug 4, to the intracellular accumulation of non-covalent inhibitors by means of an active cell uptake, as for 5 and 6. Compounds 5-6 showed similar potency and duration of inhibition of EGFR autophosphorylation as the covalent inhibitor 2, while being devoid of reactive groups forming covalent bonds with protein thiols.
Long-lasting inhibition of EGFR autophosphorylation in A549 tumor cells by intracellular accumulation of non-covalent inhibitors / Vacondio, Federica; Carmi, Caterina; Elena, Galvani; Bassi, Michele; Silva, Claudia; Lodola, Alessio; Rivara, Silvia; Cavazzoni, Andrea; Alfieri, Roberta; Petronini, Pier Giorgio; Mor, Marco. - In: BIOORGANIC & MEDICINAL CHEMISTRY LETTERS. - ISSN 0960-894X. - 23:(2013), pp. 5290-5294. [10.1016/j.bmcl.2013.08.008]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11381/2648462
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