Development of Furanopyrimidine-Based Orally Active Third-Generation EGFR Inhibitors for the Treatment of Non-Small Cell Lung Cancer

Abstract

The development of orally bioavailable, furanopyrimidine-based double-mutant (L858R/T790M) EGFR inhibitors is described. First, selectivity for mutant EGFR was accomplished by replacing the (<i>S</i>)-2-phenylglycinol moiety of <b>12</b> with either an ethanol or an alkyl substituent. Then, the cellular potency and physicochemical properties were optimized through insights from molecular modeling studies by implanting various solubilizing groups in phenyl rings A and B. Optimized lead <b>52</b> shows 8-fold selective inhibition of H1975 (EGFR^L858R/T790M overexpressing) cancer cells over A431 (EGFR^WT overexpressing) cancer cells; western blot analysis further confirmed EGFR mutant-selective target modulation inside the cancer cells by <b>52</b>. Notably, <b>52</b> displayed <i>in vivo</i> antitumor effects in two different mouse xenograft models (BaF3 transfected with mutant EGFR and H1975 tumors) with TGI = 74.9 and 97.5% after oral administration (<i>F</i> = 27%), respectively. With an extraordinary kinome selectivity (<i>S</i>(10) score of 0.017), <b>52</b> undergoes detailed preclinical development.