Conformational Constrained 4-(1-Sulfonyl-3-indol)yl-2-phenylaminopyrimidine Derivatives as New Fourth-Generation Epidermal Growth Factor Receptor Inhibitors Targeting T790M/C797S Mutations
Hao Chen, Mengzhen Lai, Tao Zhang, Yuqing Chen, Linjiang Tong, Sujie Zhu, Yang Zhou, Xiaomei Ren, Jian Ding, Hua Xie, Xiaoyun Lu, Ke Ding
Abstract
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 T790M/C797S 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 T790M/C797S inhibitors by using a macrocyclization strategy. Representative compound 18j potently inhibited EGFR 19del/T790M/C797S and EGFR L858R/T790M/C797S mutants with IC 50 values of 15.8 and 23.6 nM and suppressed Ba/F3-EGFR L858R/T790M/C797S and Ba/F3-EGFR 19del/T790M/C797S cells with IC 50 values of 0.036 and 0.052 μM, respectively, which is 10–20-fold more potent than brigatinib. 18j also potently inhibited the EGFR 19del/T790M/C797S -mutated PC-9-OR NSCLC cell proliferation with an IC 50 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 C797S -mediated resistance in NSCLC patients.