Chromenone derivatives are synthesized and evaluated as inhibitors of chromosome region maintenance 1-mediated nuclear export, targeting glioblastoma cells. Active compounds demonstrate structure- and dose-dependent inhibition, supported by structure–activity relationships and molecular docking studies. Selected analogs induce nuclear retention of endogenous proteins, show selective cytotoxicity against glioblastoma cell lines, and highlight promising potential for targeted cancer therapy.

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. Herein, whether chromenone derivatives, known for detecting thiol-containing molecules, can function as CRM1 inhibitors is explored. Several chromenone-based derivatives are synthesized and it is demonstrated that they inhibit CRM1-driven nuclear export in a structure- and dose-dependent manner. A preliminary structure–activity relationship is established, providing a rationale for selective CRM1 binding based on molecular docking studies. Additionally, it is showed that the active chromenone derivatives effectively inhibit the nuclear export of endogenous nuclear export signal-containing substrates in GBM cells. Several of these compounds exhibit selective cytotoxicity against GBM cell lines, highlighting their potential as targeted therapies for GBM.