大环化策略在EGFR抑制剂研发领域的最新进展
Recent Advances in Macrocyclic Strategies for EGFR Inhibitor Development
DOI: 10.12677/hjmce.2026.142013, PDF,   
作者: 陈士超, 周庆发*：中国药科大学理学院，江苏 南京
关键词: 大环化；EGFR抑制剂；耐药性；Macrocyclization； EGFR Inhibitor； Drug Resistance
摘要: 针对奥希替尼耐药(尤其是C797S突变)导致的治疗困境，第四代EGFR抑制剂的研发重点已从“抑制突变”转向“在高ATP竞争环境中实现高效且选择性抑制”。大环化策略通过构象限制，将分子预组织为活性构象，降低结合熵损失，提升对EGFR三重突变体的抑制效力与选择性。本文综述了BI-4020、4-吲哚基-2-苯胺基嘧啶和二氨基嘧啶三类大环抑制剂的设计逻辑与优化路径，展示了大环化在解决“效力–选择性–细胞活性”协同优化中的关键作用，并讨论了其面临的构象可预测性、成药性与合成复杂度等挑战。
Abstract: Addressing the therapeutic challenges posed by osimertinib resistance (particularly the C797S mutation), the development focus of fourth-generation EGFR inhibitors has shifted from “mutation inhibition” to “achieving potent and selective inhibition in high ATP-competitive environments.” Macrocyclic strategies pre-organize molecules into active conformations through conformational constraints, reducing binding entropy loss and enhancing inhibitory potency and selectivity against triple-mutant EGFR. This review summarizes the design rationale and optimization pathways for three classes of macrocyclic inhibitors—BI-4020, 4-indolyl-2-anilino-pyrimidine, and diamino-pyrimidine. It demonstrates macrocyclization’s pivotal role in synergistically optimizing “potency-selectivity-cell activity” and discusses challenges including conformational predictability, drugability, and synthetic complexity.
文章引用：陈士超, 周庆发. 大环化策略在EGFR抑制剂研发领域的最新进展[J]. 药物化学, 2026, 14(2): 127-138. https://doi.org/10.12677/hjmce.2026.142013

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