Design, Synthesis, and Biological Evaluation of Novel Diaminopyrimidine Macrocycles as Fourth Generation Reversible EGFR Inhibitors That Overcome Clinical Resistance to Osimertinib Mediated by C797S Mutation

Overcoming clinical resistance to osimertinib mediated by the tertiary C797S mutation remains an unmet medical need. To date, there are no effective drugs that have been approved for patients who harbor EGFRT790M/C797S mutations. Herein, we applied a structure-based drug design strategy to discover a series of potent and selective diaminopyrimidine macrocycles as novel EGFRT790M/C797S inhibitors. The representative compound 21v potently inhibited EGFR19del/T790M/C797S and EGFRL858R/T790M/C797S mutants with IC50 values of 2.3 nM and 12.5 nM, respectively, and exhibited antiproliferative activity against Ba/F3-EGFR19del/T790M/C797S and Ba/F3-EGFRL858R/T790M/C797S cells with IC50 values of 41 and 52 nM, respectively. Further, 21v inhibited proliferation of the EGFR19del/T790M/C797S mutant PC-9-OR NSCLC cell line with an IC50 value of 56 nM and displayed selectivity over parental Ba/F3 and A431 cells. Moreover, 21v exhibited antitumor efficacy in a Ba/F3-EGFR19del/T790M/C797S xenograft model. This study provides a promising macrocyclic lead for anticancer drug discovery overcoming EGFRC797S mutation mediated resistance in NSCLC patients.