在不同的肿瘤中，粘着斑激酶（FAK）（一种非受体酪氨酸激酶）的表达上调，因此它代表了癌症治疗的一个有希望的靶点。然而，FAK激酶抑制剂的开发面临着许多挑战。因此，迫切需要迅速鉴定出新的、有效的 FAK 激酶抑制剂。通过分子对接鉴定了靶向 FAK 的小分子，并通过表面等离子共振 (SPR) 和细胞热位移分析进行了验证。我们使用 CCK-8、集落形成、EdU 和 Transwell 测定以及细胞周期分析研究了 FAK 激酶抑制剂的药理作用。通过免疫共沉淀、RNA Pull-down和RNA免疫沉淀等方法确定了其分子机制。在这里，我们确认了地奥司明（Dio）是FAK的抑制剂，并证明了其在肺腺癌中的抗增殖和抗转移作用。从机制上讲，Dio 通过阻碍 FAK 的催化活性来抑制肿瘤增殖和转移。 Dio激活泛素蛋白酶体途径诱导Cyclin D1降解，同时通过降低Snail的mRNA稳定性来抑制肿瘤增殖并逆转上皮间质转化（EMT）过程，从而抑制癌症转移。此外，Dio对肺腺癌的抑制作用在小鼠异种移植模型中得到了验证。这些结果支持FAK通过稳定Cyclin D1和Snail而在肺腺癌中发挥促肿瘤作用，并表明Dio是FAK抑制的有前途的候选者。版权所有 © 2024 爱思唯尔有限公司。版权所有。

In different tumours, focal adhesion kinase (FAK), a nonreceptor tyrosine kinase, is upregulated and hence, it represents a promising target for cancer therapy. However, the development of FAK kinase inhibitors has faced a number of challenges. It is therefore imperative that new, effective FAK kinase inhibitors be identified promptly.Small molecules that target FAK were identified through molecular docking and validated through surface plasmon resonance (SPR) and cell thermal shift analysis. We investigated the pharmacological effects of FAK kinase inhibitors using CCK-8, colony formation, EdU, and Transwell assays and cell cycle analysis. The molecular mechanism was determined via methods such as coimmunoprecipitation, RNA pull-down and RNA immunoprecipitation.Here, we confirmed that diosmin (Dio) is an inhibitor of FAK and demonstrated its anti-proliferative and anti-metastatic effects in lung adenocarcinoma. Mechanistically, Dio inhibited tumour proliferation and metastasis by impeding the catalytic activity of FAK. Dio activated the ubiquitin proteasome pathway to induce Cyclin D1 degradation, while inhibiting tumour proliferation and reversing the epithelial mesenchymal transition (EMT) process by reducing the mRNA stability of Snail, thereby inhibiting cancer metastasis. In addition, the inhibitory effect of Dio on lung adenocarcinoma was validated in a mouse xenograft model.These results support the tumour-promoting role of FAK in lung adenocarcinoma by stabilizing Cyclin D1 and Snail and suggest that Dio is a promising candidate for FAK inhibition.Copyright © 2024 Elsevier GmbH. All rights reserved.