Chromenone derivatives as CRM1 Inhibitors for Targeting Glioblastoma.

Glioblastoma (GBM) is one of the most aggressive and deadly cancers. Due to the complexity and redundancy within signaling networks in GBM, targeted inhibitors of specific pathways have shown only limited success. The nuclear export receptor Chromosome Region Maintenance 1 (CRM1) has recently emerged as a promising therapeutic target, as its inhibition can simultaneously disrupt multiple key oncogenic drivers. In this study, we explore whether chromenone derivatives, known for detecting thiol-containing molecules, can function as CRM1 inhibitors. We synthesized several chromenone-based derivatives and demonstrated that they inhibit CRM1-driven nuclear export in a structure- and dose-dependent manner. A preliminary structure-activity relationship (SAR) was established, providing a rationale for selective CRM1 binding based on molecular docking studies. Additionally, we showed that the active chromenone derivatives effectively inhibit the nuclear export of endogenous nuclear export signal (NES)-containing substrates in glioblastoma cells. Several of these compounds exhibit selective cytotoxicity against glioblastoma cell lines, highlighting their potential as targeted therapies for GBM.