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

Abstract

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.

Coordinated activation of c-Src and FOXM1 drives tumor cell proliferation and breast cancer progression

“…We obtained similar results using NB-55 and NB-115, compounds that bind FOXM1 with high specificity and nanomolar affinity, enhancing its susceptibility to proteolysis and triggering proteasomal degradation (52). Similar to observations from myeloma, breast and ovarian cancer models (49,(53)(54)(55), both drugs caused dose-dependent suppression of proliferation and Foxm1 expression, while altering gene expression in a manner consistent with Foxm1 inhibition (Figure 6, D-F and Supplemental Figure 7, D and E). As with Foxm1 silencing, the response of c-Src-deficient cells to Foxm1 inhibition was markedly weaker, arguing that Foxm1 activity is largely compromised by prior loss of c-Src.…”