Synthesis and biological evaluation of 4-anilinoquinolines as potent inhibitors of epidermal growth factor receptor.

The mutant receptor tyrosine kinase EGFR is a validated and therapeutically amenable target for genotypically selected lung cancer patients. Here we present the synthesis and biological evaluation of a series of 6- and 7-substituted 4-anilinoquinolines as potent type I inhibitors of clinically relevant mutant variants of EGFR. Quinolines 3a and 3e were found to be highly active kinase inhibitors in biochemical assays and were further investigated for their biological effect on EGFR-dependent Ba/F3 cells and non-small cell lung cancer (NSCLC) cell lines.

Chemogenomic profiling provides insights into the limited activity of irreversible EGFR Inhibitors in tumor cells expressing the T790M EGFR resistance mutation.

Reversible epidermal growth factor receptor (EGFR) inhibitors are the first class of small molecules to improve progression-free survival of patients with EGFR-mutated lung cancers. Second-generation EGFR inhibitors introduced to overcome acquired resistance by the T790M resistance mutation of EGFR have thus far shown limited clinical activity in patients with T790M-mutant tumors. In this study, we systematically analyzed the determinants of the activity and selectivity of the second-generation EGFR inhibitors.

Synthesis of highly functionalized 2(1H)-pyrazinone 3-carboxamide scaffolds.

Synthesis of highly functionalized 2(1H)-pyrazinone 3-carboxamide derivatives is reported. A one-pot, two-step process including the base-mediated reaction of N,N-disubstituted aminoacetonitrile derivatives 18 with 3,5-dihalo-2(1H)-pyrazinones 1 afforded substituted aminoacetonitrile pyrazinone derivative 19, which on subsequent oxidation followed by transamidation of the resulting intermediate with primary or secondary amines gave the corresponding highly functionalized 2(1H)-pyrazinone 3-carboxamide derivatives 21.