卵巢癌（OC）是最致命的妇科恶性肿瘤，迫切需要有效的治疗药物。粘着斑激酶（FAK）在多种实体瘤中过度表达，可作为卵巢癌的潜在生物标志物。然而，目前还没有针对 FAK 的已上市药物。因此，新型FAK抑制剂的开发是治疗卵巢癌的新兴方法。在这项工作中，我们鉴定了一种选择性 FAK 抑制剂 E2，它对 FAK 具有高抑制效力。此外，E2对卵巢癌细胞具有细胞毒、抗侵袭和抗迁移活性。从机制上讲，E2处理后，FAK下游信号级联（例如Src和AKT）被抑制，从而导致卵巢癌细胞停滞在G0/G1期并诱导细胞毒性自噬。此外，E2还能减弱PA-1和ES-2卵巢癌皮下异种移植物的肿瘤生长，并抑制OVCAR3-luc的腹膜转移。此外，E2 表现出良好的药代动力学特性。总而言之，这些研究结果表明，E2 是一种选择性 FAK 抑制剂，在体内和体外均具有有效的抗卵巢癌活性，为 OC 治疗策略提供了新的可能性。版权所有 © 2024。由 Elsevier Inc. 出版。

Ovarian cancer (OC) is the deadliest form of the gynecologic malignancies and effective therapeutic drugs are urgently needed. Focal adhesion kinase (FAK) is overexpressed in various solid tumors, and could serve as a potential biomarker of ovarian cancer. However, there are no launched drugs targeting FAK. Hence, the development of the novel FAK inhibitors is an emerging approach for the treatment of ovarian cancer. In this work, we characterized a selective FAK inhibitor E2, with a high inhibitory potency toward FAK. Moreover, E2 had cytotoxic, anti-invasion and anti-migration activity on ovarian cancer cells. Mechanistically, after treatment with E2, FAK downstream signaling cascades (e.g., Src and AKT) were suppressed, thus resulting in the ovarian cancer cell arrest at G0/G1 phase and the induction of cytotoxic autophagy. In addition, E2 attenuated the tumor growth of PA-1 and ES-2 ovarian cancer subcutaneous xenografts, as well as suppressed peritoneal metastasis of OVCAR3-luc. Furthermore, E2 exhibited favorable pharmacokinetic properties. Altogether, these findings demonstrate that E2 is a selective FAK inhibitor with potent anti-ovarian cancer activities both in vivo and in vitro, offering new possibilities for OC treatment strategies.Copyright © 2024. Published by Elsevier Inc.