Laboratory of Emergency Medicine, Department of Emergency Medicine, Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China.
College of Pharmacy, National & Local Joint Engineering Research Center of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, Chongqing University of Arts and Sciences, Chongqing, 402160, China.
Eur J Med Chem. 2022 Jan 15;228:113978. doi: 10.1016/j.ejmech.2021.113978. Epub 2021 Nov 11.
Focal adhesion kinase (FAK) promotes tumor progression by intracellular signal transduction and regulation of gene expression and protein turnover, which is a compelling therapeutic target for various cancer types, including ovarian cancer. However, the clinical responses of FAK inhibitors remain unsatisfactory. Here, we describe the discovery of FAK inhibitors using a scaffold hopping strategy. Structure-activity relationship (SAR) exploration identified 36 as a potent FAK inhibitor, which exhibited inhibitory activities against FAK signaling in vitro. Treatment with 36 not only decreased migration and invasion of PA-1 cells, but also reduced expression of MMP-2 and MMP-9. Moreover, 36 inhibited tumor growth and metastasis, and no obvious adverse effects were observed during the in vivo study. These results revealed the potential of FAK inhibitor 36 for treatment of ovarian cancer.
黏着斑激酶（FAK）通过细胞内信号转导和基因表达及蛋白周转率的调节促进肿瘤进展，是包括卵巢癌在内的多种癌症类型的一个极有吸引力的治疗靶点。然而，FAK 抑制剂的临床反应仍不尽如人意。在这里，我们描述了使用支架跳跃策略发现 FAK 抑制剂。结构-活性关系（SAR）探索确定 36 是一种有效的 FAK 抑制剂，其在体外对 FAK 信号具有抑制活性。用 36 处理不仅降低了 PA-1 细胞的迁移和侵袭，而且还降低了 MMP-2 和 MMP-9 的表达。此外，36 抑制肿瘤生长和转移，在体内研究中未观察到明显的不良反应。这些结果表明 FAK 抑制剂 36 具有治疗卵巢癌的潜力。
