Ahmad Iqrar, Patel Harun M
Department of Pharmaceutical Chemistry, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, India.
Drug Dev Res. 2025 Feb;86(1):e70036. doi: 10.1002/ddr.70036.
The remarkable clinical success of third-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) has significantly advanced the treatment landscape for non-small-cell lung cancer (NSCLC). However, the emergence of the tertiary point mutation C797S poses a substantial obstacle to their clinical efficacy, leading to a dearth of FDA-approved targeted therapies for patients harboring this mutation. Addressing this pressing clinical challenge necessitates the development of novel therapeutic agents targeting the clinically challenging EGFR mutation. This review delves into the design strategies, antitumor activity, and crucial protein-drug interactions of recently introduced Orthoallosteric fourth-generation EGFR-TKIs. These inhibitors are distinguished by their ability to simultaneously engage both the canonical orthosteric (ATP) binding site and the allosteric site. By shedding light on these key aspects, the review serves as a valuable resource for medicinal chemists, empowering them to propel the advancement of fourth-generation EGFR inhibitors.
第三代表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKIs）在临床上取得的显著成功极大地推动了非小细胞肺癌（NSCLC）治疗格局的发展。然而，三级点突变C797S的出现对其临床疗效构成了重大障碍，导致缺乏FDA批准的针对携带此突变患者的靶向治疗方法。应对这一紧迫的临床挑战需要开发针对具有临床挑战性的EGFR突变的新型治疗药物。本综述深入探讨了最近推出的变构第四代EGFR-TKIs的设计策略、抗肿瘤活性以及关键的蛋白-药物相互作用。这些抑制剂的特点是能够同时作用于经典的正构（ATP）结合位点和变构位点。通过阐明这些关键方面，本综述为药物化学家提供了宝贵的资源，助力他们推动第四代EGFR抑制剂的发展。
