Das Debasis, Xie Lingzhi, Hong Jian
Discovery Chemistry Research, Arromax Pharmatech Co. Ltd., Sangtiandao Science Innovation Park No. 1 Huayun Road, SIP Suzhou 215123 P. R. China
RSC Med Chem. 2024 Aug 30;15(10):3371-94. doi: 10.1039/d4md00384e.
Lung cancer is a leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) accounts for the major portion (80-85%) of all lung cancer cases. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are commonly used as the targeted therapy for -mutated NSCLC. The FDA has approved first-, second- and third-generation EGFR-TKIs as therapeutics options. Osimertinib, the third-generation irreversible EGFR-TKI, has been approved for the treatment of NSCLC patients with the EGFR mutation. However, due to the EGFR mutation in the kinase domain of EGFR, resistance to osimertinib is observed and that limits the long-term effectiveness of the drug. The C797S mutation is one of the major causes of drug resistance against the third-generation EGFR TKIs. The C797S mutations including EGFR double mutations (19Del/C797S or L858R/C797S) and or EGFR triple mutations (19Del/T790M/C797S or L858R/T790M/C797S) cause major resistance to the third-generation EGFR-TKIs. Therefore, the discovery and development of fourth-generation EGFR-TKIs to target triple mutant EGFR with C797S mutation is a challenging topic in medicinal chemistry research. In this review, we discuss the discovery of novel fourth-generation EGFR TKIs, medicinal chemistry approaches and the strategies to overcome the C797S mutations. activities of EGFR-TKIs (2019-2024) against mutant EGFR TK, anti-proliferative activities, structural modifications, binding modes of the inhibitors and efficacies in animal models are discussed here.
肺癌是全球癌症相关死亡的主要原因。非小细胞肺癌（NSCLC）占所有肺癌病例的主要部分（80-85%）。表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKIs）通常用作针对突变型NSCLC的靶向治疗。美国食品药品监督管理局（FDA）已批准第一代、第二代和第三代EGFR-TKIs作为治疗选择。奥希替尼是第三代不可逆EGFR-TKI，已被批准用于治疗具有EGFR突变的NSCLC患者。然而，由于EGFR激酶结构域中的EGFR突变，观察到对奥希替尼的耐药性，这限制了该药物的长期有效性。C797S突变是对第三代EGFR TKIs耐药的主要原因之一。C797S突变包括EGFR双突变（19Del/C797S或L858R/C797S）和/或EGFR三突变（19Del/T790M/C797S或L858R/T790M/C797S），会导致对第三代EGFR-TKIs产生主要耐药性。因此，发现和开发针对具有C797S突变的三重突变EGFR的第四代EGFR-TKIs是药物化学研究中的一个具有挑战性的课题。在这篇综述中，我们讨论了新型第四代EGFR TKIs的发现、药物化学方法以及克服C797S突变的策略。本文还讨论了EGFR-TKIs（2019-2024年）针对突变型EGFR TK的活性、抗增殖活性、结构修饰、抑制剂的结合模式以及在动物模型中的疗效。
