Solvent-front mutations have emerged as a common mechanism leading to acquired resistance to kinase inhibitors, representing a major challenge in the clinic. Several new-generation kinase inhibitors targeting solvent-front mutations have either been approved or advanced to clinical trials. However, there remains a need to discover effective, new-generation inhibitors. In this Perspective, we systematically summarize the general types of solvent-front mutations across the kinome and describe the development of inhibitors targeting some key solvent-front mutations. Additionally, we highlight the challenges and opportunities for the next generation of kinase inhibitors directed toward overcoming solvent-front mutations.

中文翻译：

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针对激酶药物发现的溶剂前突变：从结构基础到设计策略


溶剂前突变已成为导致对激酶抑制剂获得性耐药的常见机制，这是临床上的一项重大挑战。几种针对溶剂前沿突变的新一代激酶抑制剂已获得批准或进入临床试验。然而，仍然需要发现有效的新一代抑制剂。在本视角中，我们系统地总结了整个激酶组中溶剂前部突变的一般类型，并描述了针对一些关键溶剂前部突变的抑制剂的开发。此外，我们强调了下一代激酶抑制剂旨在克服溶剂前沿突变的挑战​​和机遇。