A new class of thiodiphenylpyrimidine analogs (Thio-DPPY) were synthesized as potent and selective EGFR T790M inhibitors to overcome gefitinib resistance in nonsmall cell lung cancer (NSCLC). This structural optimization led to the identification of two potent EGFRT790M/L858R inhibitors, 14a and 14e, which possess IC50 values of 27.5 and 9.1 nM, respectively. Moreover, compounds 14a (SI > 36.4) and 14e (SI > 109.9) exhibited high selectivity and low activity against the wild-type EGFR (IC50 > 1,000 nM). In particular, compound 14a also displayed strong potency against EGFRT790M -mutated H1975 cells (IC50 = 0.074 μM), but weak activity toward normal cells HBE (IC50 > 40 μM) and LO-2 (IC50 = 9.891 μM). It is important that compound 14a (SI = 52.6) significantly improved the selectivity against mutant H1975 cells over wild-type A431 cells than rociletinib (SI = 6.0), thus revealing its slight cell cytotoxicity. This study provides a promising Thio-DPPY derivative as enhanced EGFR T790M inhibitor, and also revealed valuable clues for further optimization of DPPY scaffold to overcome NSCLC resistance.
Keywords: EGFR T790M; NSCLC; inhibitors; pyrimidine; resistance.
© 2018 John Wiley & Sons A/S.