Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China.
J Med Chem. 2020 Dec 10;63(23):14382-14403. doi: 10.1021/acs.jmedchem.0c01248. Epub 2020 Oct 15.
Focal adhesion kinase (FAK) is a nonreceptor intracellular tyrosine kinase that plays an essential role in cancer cell adhesion, survival, proliferation, and migration through both its enzymatic activities and scaffolding functions. Overexpression of FAK has been found in many human cancer cells from different origins, which promotes tumor progression and influences clinical outcomes in different classes of human tumors. Therefore, FAK has been considered as a promising target for small molecule anticancer drug development. Many FAK inhibitors targeting different domains of FAK with various mechanisms of functions have been reported, including kinase domain inhibitors, FERM domain inhibitors, and FAT domain inhibitors. In addition, FAK-targeting PROTACs, which can induce the degradation of FAK, have also been developed. In this Perspective, we summarized the progress in the development of small molecular FAK inhibitors and proposed the perspectives for the future development of agents targeting FAK.
黏着斑激酶（FAK）是一种非受体细胞内酪氨酸激酶，通过其酶活性和支架功能，在癌细胞黏附、存活、增殖和迁移中发挥重要作用。在不同来源的许多人类癌细胞中都发现了 FAK 的过表达，这促进了肿瘤的进展，并影响了不同类型人类肿瘤的临床结局。因此，FAK 已被认为是小分子抗癌药物开发的一个有前途的靶点。已经报道了许多针对 FAK 不同结构域的靶向 FAK 的小分子抑制剂，具有不同的作用机制，包括激酶结构域抑制剂、FERM 结构域抑制剂和 FAT 结构域抑制剂。此外，还开发了靶向 FAK 的 PROTACs，它可以诱导 FAK 的降解。在这篇观点文章中，我们总结了小分子 FAK 抑制剂的发展进展，并对未来靶向 FAK 的药物的发展提出了展望。
