Chemical Biology Research Center at School of Pharmaceutical Sciences , Wenzhou Medical University , Wenzhou , Zhejiang 325035 , China.
School of Chemical Engineering , Nanjing University of Science and Technology , Nanjing , Jiangsu 210094 , China.
J Med Chem. 2018 May 24;61(10):4290-4300. doi: 10.1021/acs.jmedchem.7b01310. Epub 2017 Nov 27.
The epidermal growth factor receptor (EGFR) has been a particular interest for drug development for treatment of non-small-cell lung cancer (NSCLC). The current third-generation EGFR small-molecule inhibitors, especially osimertinib, are at the forefront clinically for treatment of patients with NSCLC. However, a high percentage of these treated patients developed a tertiary cystein-797 to serine-790 (C797S) mutation in the EGFR kinase domain. This C797S mutation is thought to induce resistance to all current irreversible EGFR TKIs. In this Miniperspective, we present key mechanisms of resistance in response to third-generation EGFR TKIs, and emerging reports on novel EGFR TKIs to combat the resistance. Specifically, we analyze the allosteric and ATP-competitive inhibitors in terms of drug discovery, binding mechanism, and their potency and selectivity against EGFR harboring C797S mutations. Lastly, we provide some perspectives on new challenges and future directions in this field.
表皮生长因子受体（EGFR）一直是开发用于治疗非小细胞肺癌（NSCLC）药物的特别关注点。目前的第三代 EGFR 小分子抑制剂，特别是奥希替尼，在治疗 NSCLC 患者方面处于临床前沿。然而，这些接受治疗的患者中很大一部分在 EGFR 激酶结构域中出现了三级半胱氨酸 797 到丝氨酸 790（C797S）突变。这种 C797S 突变被认为会导致对所有现有的不可逆 EGFR TKI 的耐药性。在这篇简评中，我们介绍了针对第三代 EGFR TKI 的耐药性的关键机制，以及针对该耐药性的新型 EGFR TKI 的最新报告。具体而言，我们分析了变构和 ATP 竞争性抑制剂在药物发现、结合机制以及对携带 C797S 突变的 EGFR 的效力和选择性方面的情况。最后，我们对该领域的新挑战和未来方向提供了一些观点。
