Focal adhesion kinase (FAK) is considered as a pivotal intracellular non-receptor tyrosine kinase, and has garnered significant attention as a promising target for anticancer drug development. As of early 2024, a total of 12 drugs targeting FAK have been approved for clinical or preclinical studies worldwide, including three PROTAC degraders. In recent three years (2021–2023), significant progress has been made in designing targeted FAK anticancer agents, including the development of a novel benzenesulfofurazan type NO-releasing FAK inhibitor and the first-in-class dual-target inhibitors simultaneously targeting FAK and HDACs. Given the pivotal role of FAK in the discovery of anticancer drugs, as well as the notable advancements achieved in FAK inhibitors and PROTAC degraders in recent years, this review is underbaked to present a comprehensive overview of the function and structure of FAK. Additionally, the latest findings on the inhibitors and PROTAC degraders of FAK from the past three years, along with their optimization strategies and anticancer activities, were summarized, which might help to provide novel insights for the development of novel targeted FAK agents with promising anticancer potential and favorable pharmacological profiles.

中文翻译：

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癌症治疗中靶向黏着斑激酶 （FAK）：抑制剂和 PROTAC 降解剂的最新进展


黏着斑激酶 （FAK） 被认为是一种关键的细胞内非受体酪氨酸激酶，作为抗癌药物开发的有前途的靶点而受到广泛关注。截至 2024 年初，全球共有 12 种靶向 FAK 的药物被批准用于临床或临床前研究，其中包括 3 种 PROTAC 降解剂。近三年（2021-2023 年），靶向 FAK 抗癌药物的设计取得了重大进展，包括开发新型苯磺基呋喃赞型 NO 释放 FAK 抑制剂和同时靶向 FAK 和 HDAC 的同类首创双靶点抑制剂。鉴于 FAK 在抗癌药物发现中的关键作用，以及近年来 FAK 抑制剂和 PROTAC 降解剂取得的显着进展，本文未全面概述 FAK 的功能和结构。此外，总结了过去三年关于 FAK 抑制剂和 PROTAC 降解剂的最新发现，以及它们的优化策略和抗癌活性，这可能有助于为开发具有前景的抗癌潜力和良好药理学特征的新型靶向 FAK 药物提供新的见解。