Discovery of Potent and Wild-Type-Sparing Fourth-Generation EGFR Inhibitors for Treatment of Osimertinib-Resistance NSCLC

Abstract

Osimertinib resistance is an unmet clinical need for the treatment of non-small cell lung cancer (NSCLC), and the main mechanism is tertiary C797S mutation of epidermal growth factor receptor (EGFR). To date, there is no inhibitor approved for the treatment of Osimertinib-resistant NSCLC. Herein, we reported a series of Osimertinib derivatives as fourth-generation inhibitors which were rationally designed. Top candidate D51 potently inhibited the EGFRL858R/T790M/C797S mutant with an IC50 value of 14 nM and suppressed the proliferation of H1975-TM cells with an IC50 value of 14 nM, which show over 500-fold selectivity against wild-type forms. Moreover, D51 inhibited the EGFRdel19/T790M/C797S mutant and the proliferation of the PC9-TM cell line with IC50 values of 62 and 82 nM. D51 also exhibited favorable in vivo druggability, including PK parameters, safety properties, in vivo stability, and antitumor activity.

Design, Synthesis, and Biological Evaluation of Novel EGFR PROTACs Targeting C797S Mutation

“…Due to the lack of marketed small-molecule drugs targeting EGFR C797S mutation, our previous work has identified compound D51 as an effective EGFR inhibitor targeting C797S mutation. 30 Therefore, we chose to modify D51 as an EGFR ligand to design PROTACs. First, the docking model showed that the N,N-dimethylethanamine side chain of D51 was exposed to the solvent region, indicating that this site could be used for linker anchoring (Figure 3A).…”

“…First, the docking model showed that the N,N-dimethylethanamine side chain of D51 was exposed to the solvent region, indicating that this site could be used for linker anchoring (Figure 3A). 30 To promote the exposure of this part to the solvent region, we replaced the flexible dimethylethanamine with a rigid piperazine ring (compound 6). The docking model showed that compound 6 retained a tight interaction with EGFR T790M/C797S , with the piperazine fully exposed to the solvent region (Figure 3B).…”

“…Due to the lack of marketed small-molecule drugs targeting EGFR C797S mutation, our previous work has identified compound D51 as an effective EGFR inhibitor targeting C797S mutation . Therefore, we chose to modify D51 as an EGFR ligand to design PROTACs.…”

“…Therefore, we chose to modify D51 as an EGFR ligand to design PROTACs. First, the docking model showed that the N , N -dimethylethanamine side chain of D51 was exposed to the solvent region, indicating that this site could be used for linker anchoring (Figure A) . To promote the exposure of this part to the solvent region, we replaced the flexible dimethylethanamine with a rigid piperazine ring (compound 6 ).…”

Targeted Strategies for Degradation of Key Transmembrane Proteins in Cancer

“…Allosteric inhibitors were active against EGFRL858R/T790M/C797S mutants, and these compounds were proposed as fourth-generation drug candidates [ 61 , 62 , 63 , 64 ]. Non-allosteric molecules were also developed with activity against osimertinib-resistant NSCLC, characterized by broad molecular heterogeneity, and EGFRL858R/T790M/C797S mutant cells [ 65 ]. However, allosteric compounds can still induce drug-resistant mutations due to a similar strategy of inhibiting the EGFR ATP-binding site.…”