Design, synthesis and biological evaluation of WZ4002 analogues as EGFR inhibitors.

A series of thirty two anilinopyrimidines derived from WZ4002 has been synthesized and evaluated for percentage inhibition of six different EGFR kinases using LanthaScreen binding assay method (EGFR d746 – 750) or Z’LYTE assay method (EGFR-WT, EGFR d746 – 750, EGFR T790M, EGFR T790M L858R, EGFR C797S and EGFR T790M L858R C797S). Ortho -hydroxyacetamide 10 exhibited complete inhibition of all the six kinases at 10 µM. Against the triple mutant, EGFR T790M C797S L858R, compounds 9 – 12 exhibited complete inhibition at 10 µM and nearly complete inhibition at 1 µM. The target compounds were also evaluated using the MTT assay to determine their cytotoxic activity against human non-small cell lung cancer cells (PC9, PC9GR and H460) and mouse leukemic cells (Ba/F3 WT and Ba/F3T 3151). Overall, 7 , 9 – 12 , 30 and 31 were found to be the most potent compounds across all five cell lines. [ABSTRACT FROM AUTHOR]