Structural optimization of diphenylpyrimidine scaffold as potent and selective epidermal growth factor receptor inhibitors against L858R/T790M resistance mutation in nonsmall cell lung cancer.

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 EGFR inhibitors, 14a and 14e, which possess IC 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 (IC  > 1,000 nM). In particular, compound 14a also displayed strong potency against EGFR -mutated H1975 cells (IC  = 0.074 μM), but weak activity toward normal cells HBE (IC  > 40 μM) and LO-2 (IC  = 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.