Pyrimido[4,5-d]pyrimidin-4(lH)-one Derivatives as Selective Inhibitors of EGFR Threonine~(790) to Methionine~(790) (T790M) Mutants

摘要

The epidermal growth factor receptor (EGFR, erbB1, HER1) has been well-validated as a molecular target in anticancer drug discovery. In non-small-cell lung cancer patients (NSCLCs) harboring active mutations in the EGFR tyrosine kinase domain (L858R and del E746-A750), the first generation inhibitors, gefinitib and erlotinib, have achieved significant clinical benefits but emerging acquired resistance to them has become a major clinical challenge. The "gatekeeper" T790M mutation (threonine~(790) →methionine~(790)) of EGFR, by which the binding of ATP with the kinase is favored, is one of the primary mechanisms for resistance and plays a role in the circa 50 % of NSCLC patients who acquired clinical resistance. Although the Cys797-chelating irreversible EGFR inhibitors displayed promising potential to overcome EGFR~(T790M) related resistance in animal models, their non-selective inhibition against wild-type EGFR (EGFR~(WT)) and/or other kinases results in a relatively low maximal-tolerated-dose (MTD) and poor clinical outcomes in human patients. Inhibitors selectively targeting EGFR~(T790M) mutants are an attractive strategy for the clinical management of NSCLC patients with acquired resistance.