The epidermal growth factor receptor (EGFR), a tyrosine kinase receptor involved in oncogenic phenomena, is a validated target for cancer therapy.1 Gefitinib and erlotinib are the earliest small molecule EGFR tyrosine kinase inhibitors (TKIs) approved for non-small cell lung cancer (NSCLC) treatment. These compounds are able to establish a reversible interaction with the ATP binding pocket of the kinase domain. A single point mutation in the ATP binding site involving the gatekeeper residue Thr790 (T790M) prevents the ATP-competitive reversible inhibitors from binding and leads to the development of drug resistance.2 A second generation of EGFR-targeted agents allowed to overcame this resistance by irreversible interaction with the target: these compounds irreversibly alkylate a cysteine (Cys797) within the catalytic site of EGFR.4 The main limit of this class of compounds is the intrinsic reactivity due to the presence of a Michael acceptor group, responsible for the covalent bond formation with the cysteine residue. This high reactivity may give rise to unexpected toxicity and lack of target specificity.2 With the aim to reduce the undesired interactions with non-target related proteins, we substituted the highly electrophilic Michael acceptor group with a low reactive group that preserve the ability to react with the nucleophile within the target protein. For this purpose, we explored a series of β-aminocarbonyl groups, inserted on a traditional quinazoline-based driver portion, synthesizing a series of Mannich base derivatives, which had shown to be chemically stable under physiologic conditions, while retaining an irreversible inhibition of the target.

Mannich base derivatives as novel EGFR irreversible inhibitors / Russo, S.; Mor, M.; Carmi, C.; Vacondio, F.; Petronini, P.; Cavazzoni, A.. - (2011). ((Intervento presentato al convegno 10th ULLA Summer School tenutosi a Parma nel July 2-8, 2011.

Mannich base derivatives as novel EGFR irreversible inhibitors

RUSSO, Simonetta;MOR, Marco;CARMI, Caterina;VACONDIO, Federica;PETRONINI, Pier Giorgio;CAVAZZONI, Andrea
2011

Abstract

The epidermal growth factor receptor (EGFR), a tyrosine kinase receptor involved in oncogenic phenomena, is a validated target for cancer therapy.1 Gefitinib and erlotinib are the earliest small molecule EGFR tyrosine kinase inhibitors (TKIs) approved for non-small cell lung cancer (NSCLC) treatment. These compounds are able to establish a reversible interaction with the ATP binding pocket of the kinase domain. A single point mutation in the ATP binding site involving the gatekeeper residue Thr790 (T790M) prevents the ATP-competitive reversible inhibitors from binding and leads to the development of drug resistance.2 A second generation of EGFR-targeted agents allowed to overcame this resistance by irreversible interaction with the target: these compounds irreversibly alkylate a cysteine (Cys797) within the catalytic site of EGFR.4 The main limit of this class of compounds is the intrinsic reactivity due to the presence of a Michael acceptor group, responsible for the covalent bond formation with the cysteine residue. This high reactivity may give rise to unexpected toxicity and lack of target specificity.2 With the aim to reduce the undesired interactions with non-target related proteins, we substituted the highly electrophilic Michael acceptor group with a low reactive group that preserve the ability to react with the nucleophile within the target protein. For this purpose, we explored a series of β-aminocarbonyl groups, inserted on a traditional quinazoline-based driver portion, synthesizing a series of Mannich base derivatives, which had shown to be chemically stable under physiologic conditions, while retaining an irreversible inhibition of the target.
Mannich base derivatives as novel EGFR irreversible inhibitors / Russo, S.; Mor, M.; Carmi, C.; Vacondio, F.; Petronini, P.; Cavazzoni, A.. - (2011). ((Intervento presentato al convegno 10th ULLA Summer School tenutosi a Parma nel July 2-8, 2011.
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11381/2785994
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus ND
  • ???jsp.display-item.citation.isi??? ND
social impact