Epidermal Growth Factor Receptor Irreversible Inhibitors: Chemical Exploration of the Cysteine-Trap Portion

C.      Carmi; A.      Lodola; S.      Rivara; F.      Vacondio; A.      Cavazzoni; R.      R. Alfieri; A.      Ardizzoni; P.      G. Petronini; M.      Mor

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