Department of Respiratory and Critical Care Medicine, Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Neuro-system and Multimorbidity Laboratory, State Key Laboratory of Biotherapy and Cancer Center and State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, Sichuan University, 610041, Sichuan, China.
Department of Respiratory and Critical Care Medicine, Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Neuro-system and Multimorbidity Laboratory, State Key Laboratory of Biotherapy and Cancer Center and State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, Sichuan University, 610041, Sichuan, China; West China College of Medicine, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
Eur J Med Chem. 2024 Dec 5;279:116913. doi: 10.1016/j.ejmech.2024.116913. Epub 2024 Sep 26.
Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase frequently overexpressed in various cancer cells, facilitating tumor growth through the regulation of cell adhesion, migration, and proliferation. Consequently, targeting FAK is considered a promising anti-tumor strategy, particularly for invasive cancers. Numerous potent small-molecule inhibitors have progressed to clinical trials. Among these, Defactinib is under evaluation for regulatory approval as a treatment for ovarian serous tumors. Furthermore, novel FAK inhibitors, including PROTACs, have emerged as key research focuses, anticipated to overcome the limitations of traditional inhibitors. In this Perspective, we highlight the protein structure, biological functions, relevant signaling pathways, and associations of FAK with cancer development. We also analyze the clinical status of FAK inhibitors, paying special attention to the various classes of FAK inhibitors, with detailed analyses of their chemical structures, structure-activity relationships (SARs), bioactivity profiles, selectivity profiles, and therapeutic potentials.
黏着斑激酶（FAK）是一种在多种癌细胞中经常过表达的非受体酪氨酸激酶，通过调节细胞黏附、迁移和增殖促进肿瘤生长。因此，靶向 FAK 被认为是一种有前途的抗肿瘤策略，特别是针对侵袭性癌症。许多有效的小分子抑制剂已经进入临床试验。其中，Defactinib 正在评估用于监管批准，作为治疗卵巢浆液性肿瘤的药物。此外，新型 FAK 抑制剂，包括 PROTACs，已成为研究的重点，预计将克服传统抑制剂的局限性。在这篇观点文章中，我们强调了 FAK 的蛋白质结构、生物学功能、相关信号通路以及与癌症发展的关联。我们还分析了 FAK 抑制剂的临床状况，特别关注 FAK 抑制剂的各种类别，详细分析了它们的化学结构、构效关系（SAR）、生物活性谱、选择性谱和治疗潜力。
