Discovering potent EGFR inhibitors through the structural optimization of the Betti-base scaffold.

EGFR is a critical oncogenic driver in non-small cell lung cancer (NSCLC). However, there are no approved inhibitors for the C797S resistance mutation. Allosteric inhibitors targeting a site near the ATP-binding pocket have emerged as a promising alternative. In our previous study, we identified the Betti-base scaffold as a promising core for EGFR inhibition. This scaffold represents a structurally unique chemotype for EGFR allosteric inhibitors, clearly distinct from previously reported EGFR allosteric ligands. In this study, a series of Betti-base derivatives was optimized through the introduction of hydrophilic groups. Particularly, compound 2b exhibited markedly improved anti-proliferative effects against both H1975 (EGFR) and Ba/F-EGFR cell lines, demonstrating IC values of 3.06 ± 0.17 μM and 1.08 ± 0.11 μM, respectively, comparable to the positive control JBJ-04-125-02. 2b could suppress the phosphorylation of EGFR and induce cell apoptosis in a dose-dependent manner in both H1975 and Ba/F-EGFR cell lines. The stable binding mode of 2b in the EGFR allosteric site, as demonstrated by molecular docking and dynamics simulations, provided a structural basis for its efficacy. These findings collectively suggested that 2b was a highly promising lead compound for combating NSCLC resistance driven by the C797S mutation.