New 1,1-diarylethylene FOXM1 inhibitors potently reduce intracellular FOXM1 and suppress high-grade serous ovarian carcinoma cell viability

As an oncogenic transcription factor highly upregulated in numerous cancer types and responsible for promoting multiple hallmarks of the disease, Forkhead Box M1 (FOXM1) is a promising target for treatment against high-grade ovarian serous carcinoma (HGSC), a lethal and aggressive cancer that overexpresses FOXM1 and its transcriptional pathway. Several FOXM1 inhibitors have been established, but none have advanced to clinical trials. In this study, we report that our recently developed 1,1-diarylethylene FOXM1 inhibitors (NB compounds) potently and selectively inhibit HGSC cell viability, more so than a panel of other reported FOXM1 inhibitors. The NB compounds decreased FOXM1 expression through proteasomal degradation, which resulted in decreased expression of its downstream target cyclin B1 (CCNB1), without affecting other FOX family members. Moreover, the NB compounds exhibited robust anti-cancer effects by promoting apoptosis, suppressing colony formation more potently than other FOXM1 inhibitors, and synergizing with carboplatin to inhibit the viability of HGSC cells. Our data demonstrate that the NB compounds are promising FOXM1 inhibitors that may serve as a novel therapeutic strategy for HGSC and other cancers whose aggressive cancer biology is driven by FOXM1 and its oncogenic transcriptional pathway.