Discovery of new cyclopropane sulfonamide derivatives as EGFR inhibitors to overcome C797S-mediated resistance and EGFR double mutation

The C797S mutation of EGFR leads to Osimertinib resistance by blocking the covalent binding of Cys797. To develop new agents that can overcome EGFR mutation resistance, thirty seven new cyclopropane sulfonamide derivatives were synthesized and evaluated as EGFR^{L858R/T790M/C797S} or EGFR^{Del19/T790M/C797S} inhibitors by structure-based screening. Most of the synthesized compounds exhibit good to excellent anti proliferation activity against to BaF3-EGFR ^{L858R/T790M/C797S} and BaF3-^{C797S/Del19/T790M} Cancer cell lines. Representative compounds 8l showed inhibitory activity against the two Cancer cell lines with the IC₅₀ values of 0.0012 and 0.0013 μM, respectively. Another compound 8h, exhibited slightly lower activity (0.0042 and 0.0034 μM of the IC₅₀ values) to both of the two tri-mutation cell lines, but excellent activities against H1975 and PC9 cells with IC₅₀ values of 13 and 19 nM, respectively. Considering the acquired drug resistance of tumors is a gradual process, we chose 8h for further in vivo and mechanism study. 8h was demonstrated significantly inhibited tumor growth with 72.1 % of the TGI in the BaF3/EGFR-TM xenograft tumor model and 83.5 % in the H1975-DM xenograft tumor model. Compound 8h was confirmed to be safe with no significant side effects as showed by the results of in vitro assay of human normal cells and the sections of Animals major organs. Mechanism studies showed that in addition to inhibiting EGFR mutations, 8h can also target the tumor microenvironment and induce tumor cell Apoptosis. All these results indicate that 8h deserves further investigation as an EGFR inhibitor to overcome C797S-mediated resistance.

Cell apoptosis; EGFR/Double-mutation; EGFR/Tri-mutation; Neovascularization; Tumor microenvironment.