Conformational Constrained 4-(1-Sulfonyl-3-indol)yl-2-phenylaminopyrimidine Derivatives as New Fourth-Generation Epidermal Growth Factor Receptor Inhibitors Targeting T790M/C797S Mutations.
Chen H, Lai M, Zhang T, Chen Y, Tong L, Zhu S, Zhou Y, Ren X, Ding J, Xie H, Lu X, Ding K.
Tertiary C797S mutation of epidermal growth factor receptor (EGFR)-mediated resistance in non-small-cell-lung-cancer (NSCLC) patients is still an unmet clinical need. Several classes of adenosine 5'-triphosphate-competitive or allosteric EGFR<sup>T790M/C797S</sup> inhibitors and degraders have been developed, but none of them have received approval from the regulatory agencies. Herein, we report the structure-based design of conformational constrained 4-(1-ethylsufonyl-3-indolyl)-2-phenylaminopyrimidines as new EGFR<sup>T790M/C797S</sup> inhibitors by using a macrocyclization strategy. Representative compound <b>18j</b> potently inhibited EGFR<sup>19del/T790M/C797S</sup> and EGFR<sup>L858R/T790M/C797S</sup> mutants with IC<sub>50</sub> values of 15.8 and 23.6 nM and suppressed Ba/F3-EGFR<sup>L858R/T790M/C797S</sup> and Ba/F3-EGFR<sup>19del/T790M/C797S</sup> cells with IC<sub>50</sub> values of 0.036 and 0.052 μM, respectively, which is 10-20-fold more potent than brigatinib. <b>18j</b> also potently inhibited the EGFR<sup>19del/T790M/C797S</sup>-mutated PC-9-OR NSCLC cell proliferation with an IC<sub>50</sub> value of 0.644 μM but was less potent for parental Ba/F3 and A431 cells. This study provides a new lead compound for drug discovery to combat EGFR<sup>C797S</sup>-mediated resistance in NSCLC patients.