Abstract
Covalent EGFR irreversible inhibitors showed promising potential for the treatment of gefitinib-resistant tumors and for imaging purposes. They contain a cysteine-reactive portion forming a covalent bond with the protein. Irreversible kinase inhibitors have been advanced to clinical studies, mostly characterized by an acrylamide or butynamide warhead. However, the clinical usefulness of these compounds has been hampered by resistances, toxicity and pharmacokinetic problems. Investigation on the structure-activity and structure-reactivity relationships may provide useful information for compounds with improved selectivity and pharmacokinetic properties. This review focuses on the exploration of the cysteine-trap portions able to irreversibly inhibit EGFR and other erbB receptors.
Keywords: Antitumor, covalent inhibition, cysteine-trap, EGFR, erbB receptors, irreversible inhibitors, NSCLC, gefitinib-resistant, resistances, toxicity, pharmacokinetic
Mini-Reviews in Medicinal Chemistry
Title: Epidermal Growth Factor Receptor Irreversible Inhibitors: Chemical Exploration of the Cysteine-Trap Portion
Volume: 11 Issue: 12
Author(s): C. Carmi, A. Lodola, S. Rivara, F. Vacondio, A. Cavazzoni, R. R. Alfieri, A. Ardizzoni, P. G. Petronini and M. Mor
Affiliation:
Keywords: Antitumor, covalent inhibition, cysteine-trap, EGFR, erbB receptors, irreversible inhibitors, NSCLC, gefitinib-resistant, resistances, toxicity, pharmacokinetic
Abstract: Covalent EGFR irreversible inhibitors showed promising potential for the treatment of gefitinib-resistant tumors and for imaging purposes. They contain a cysteine-reactive portion forming a covalent bond with the protein. Irreversible kinase inhibitors have been advanced to clinical studies, mostly characterized by an acrylamide or butynamide warhead. However, the clinical usefulness of these compounds has been hampered by resistances, toxicity and pharmacokinetic problems. Investigation on the structure-activity and structure-reactivity relationships may provide useful information for compounds with improved selectivity and pharmacokinetic properties. This review focuses on the exploration of the cysteine-trap portions able to irreversibly inhibit EGFR and other erbB receptors.
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Carmi C., Lodola A., Rivara S., Vacondio F., Cavazzoni A., R. Alfieri R., Ardizzoni A., G. Petronini P. and Mor M., Epidermal Growth Factor Receptor Irreversible Inhibitors: Chemical Exploration of the Cysteine-Trap Portion, Mini-Reviews in Medicinal Chemistry 2011; 11 (12) . https://dx.doi.org/10.2174/138955711797247725
DOI https://dx.doi.org/10.2174/138955711797247725 |
Print ISSN 1389-5575 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5607 |
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