Overcoming resistance to third-generation tyrosine kinase inhibitors (TKIs) such as Osimertinib, particularly due to the emergence of the C797S mutation, remains a key challenge in non-small cell lung cancer (NSCLC) therapy. This review highlights recent advancements in the development of fourth-generation EGFR inhibitors that specifically target the catalytic Lys745 residue, aiming to overcome resistance associated with Osimertinib. Both covalent and non-covalent inhibitors targeting Lys745 were explored, using warheads like sulfonyl fluoride, phosphine oxides, esters, and trisubstituted imidazoles. Sulfonyl fluoride was particularly effective in forming covalent bonds with Lys745, while non-covalent analogues demonstrated flexibility with reduced off-target effects. The manuscript highlights the importance of warhead design, molecular docking, protein XRD study and structure-activity relationships (SAR) for optimizing Lys745-targeting inhibitors. The study suggests that hybrid scaffolds combining key pharmacophoric features from Osimertinib and Brigatinib along with Lys745 targeting warheads, could enhance selectivity and potency. Future efforts should focus on refining bioavailability, identifying new scaffolds by employing drug design strategies. Fourth-generation TKIs targeting Lys745 offer a novel therapeutic avenue, potentially overcoming mutation-induced resistance and improving NSCLC treatment outcomes. This approach represents a critical advancement toward durable clinical responses in patients with drug-resistant cancer.

中文翻译：

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第四代 EGFR 酪氨酸激酶抑制剂中的催化赖氨酸 745 靶向策略解决 C797S 突变耐药性


克服对第三代酪氨酸激酶抑制剂 （TKI） 如奥希替尼的耐药性，特别是由于 C797S 突变的出现，仍然是非小细胞肺癌 （NSCLC） 治疗的关键挑战。本文重点介绍了专门针对催化 Lys745 残基的第四代 EGFR 抑制剂开发的最新进展，旨在克服与奥希替尼相关的耐药性。使用磺酰氟、氧化膦、酯和三取代咪唑等弹头探索了靶向 Lys745 的共价和非共价抑制剂。磺酰氟在与 Lys745 形成共价键方面特别有效，而非共价类似物表现出柔韧性，脱靶效应降低。该手稿强调了弹头设计、分子对接、蛋白质 XRD 研究和构效关系 （SAR） 对优化 Lys745 靶向抑制剂的重要性。研究表明，结合奥希替尼和布加替尼的关键药效团特征以及 Lys745 靶向弹头的混合支架可以提高选择性和效力。未来的工作应侧重于提高生物利用度，通过采用药物设计策略来识别新的支架。靶向 Lys745 的第四代 TKI 提供了一种新的治疗途径，有可能克服突变诱导的耐药性并改善 NSCLC 治疗结果。这种方法代表了耐药癌症患者实现持久临床反应的关键进步。