Conformational Constrained 4‑(1-Sulfonyl-3-indol)yl-2-phenylaminopyrimidine Derivatives as New Fourth-Generation Epidermal Growth Factor Receptor Inhibitors Targeting T790M/C797S Mutations

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 EGFRT790M/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 EGFRT790M/C797S inhibitors by using a macrocyclization
strategy. Representative compound 18j potently inhibited
EGFR19del/T790M/C797S and EGFRL858R/T790M/C797S mutants with IC50 values of 15.8 and 23.6 nM and suppressed
Ba/F3-EGFRL858R/T790M/C797S and Ba/F3-EGFR19del/T790M/C797S cells with IC50 values of 0.036 and 0.052 μM, respectively,
which is 10–20-fold more potent than brigatinib. 18j also potently inhibited the EGFR19del/T790M/C797S-mutated
PC-9-OR NSCLC cell proliferation with an IC50 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
EGFRC797S-mediated resistance in NSCLC patients.