Design and synthesis of Betti base derivatives as EGFR inhibitors

EGFR serves as a critical oncogenic driver in NSCLC pathogenesis. While multiple generations of EGFR TKIs have been clinically approved, their efficacy is frequently limited by rapid drug resistance. Several EGFR allosteric inhibitors targeting a site adjacent to the ATP-binding site have been reported. The allosteric inhibitors EAI001 and EAI045 are a new type of EGFR inhibitors that bind to EGFR away from the ATP-binding site and not relying on Cys 797. In our previous work, compound ZINC49691377 (1a) was identified using the structure-based high throughput virtual screening as a novel potent Anticancer agent. In the current study, a focused library of Betti base derivatives were designed based on ZINC49691377 (1a) through substituent transformation and bioisosteric replacement. Compound 2b showed the highest antiproliferative activity against H1975 cells (IC₅₀ = 0.40 ± 0.01 μM), and significant activity against Ba/F₃-EGFR^{L858R/T790M/C797S} cells (IC₅₀ = 2.36 ± 0.33 μM). Notably, 2b treatment induced G₀/G₁ phase cell cycle arrest in H1975 cells while triggering significant Apoptosis in both H1975 and Ba/F₃-EGFR^{L858R/T790M/C797S} cell lines. Molecular docking and dynamics simulation confirmed stable binding of 2b within the allosteric pocket of EGFR. These findings demonstrated Betti base derivatives as a novel chemotype for the design of novel EGFR inhibitors.

C797S mutation; EGFR; L858R/T790M mutation; NSCLC.