A novel selective FAK inhibitor E2 inhibits ovarian cancer metastasis and growth by inducing cytotoxic autophagy

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.