ABK-EGFR-1的发现与表征：一种具有优异选择性和脑穿透性的第四代EGFR C797S抑制剂

Introduction: The EGFR C797S mutation is a clinically validated mechanism of resistance to third-generation EGFR tyrosine kinase inhibitors (TKIs) and is estimated to occur in approximately 51,000-146,000 cases annually worldwide. Currently, no approved therapies specifically target EGFR C797S-mediated resistance. Therefore, developing inhibitors that effectively target EGFR C797S and prior resistance mutations-while preserving high potency, achieving effective central nervous system (CNS) penetration, and sparing wild-type EGFR, remains a critical unmet need. Herein, we report the discovery and preclinical characterization of ABK-EGFR-1, a novel fourth-generation EGFR inhibitor designed to target EGFR C797S mutations. ABK-EGFR-1 demonstrates high selectivity over wild-type EGFR and other kinases, robust in vivo efficacy across multiple EGFR C797S-driven xenograft models, and excellent brain penetration. Methods: Anti-proliferative activity was evaluated in a panel of cell lines harboring diverse EGFR C797S mutations to assess the potency and mutation coverage of ABK-EGFR-1 in comparison with reference EGFR inhibitors. In vivo antitumor efficacy was assessed using multiple xenograft models driven by EGFR C797S mutations. Selectivity was further evaluated by comparing cellular and in vivo responses in models expressing mutant versus wild-type EGFR. In addition, kinome selectivity and drug-like properties were systematically characterized. Results: ABK-EGFR-1 potently inhibited cell proliferation across multiple EGFR C797S mutant cell lines and exhibited superior selectivity for mutant EGFR over wild-type EGFR compared with other EGFR inhibitors. In xenograft mouse models harboring various EGFR C797S mutations, oral administration of ABK-EGFR-1 resulted in strong, dose-dependent tumor growth inhibition whereas in xenograft models driven by wild-type EGFR, ABK-EGFR-1 demonstrated markedly weaker antitumor activity, further supporting its superior selectivity profile in vivo. Furthermore, ABK-EGFR-1 exhibited excellent preclinical brain penetration, favorable oral bioavailability, and a promising safety profile Conclusion: ABK-EGFR-1 is a novel next-generation EGFR C797S inhibitor with enhanced selectivity over wild-type EGFR and robust CNS penetration. It demonstrates strong in vivo efficacy across multiple EGFR C797S-driven xenograft models and possesses favorable drug-like properties. Collectively, these findings support the continued preclinical development of ABK-EGFR-1 and its advancement toward clinical evaluation.