Therapeutic horizons in targeting XPO1 with small inhibitor molecules: Recent achievements, synthetic strategies, opportunities, challenges, and future perspectives.

XPO1 governs the cytoplasmic translocation of tumor suppressors, growth regulators, and viral components from the nucleus to the cytoplasm, playing a pivotal role in cancer progression and viral replication. XPO1 inhibition has also been shown to modulate immune responses, particularly by altering NF-κB signaling and cytokine export. In oncology, these inhibitors restore nuclear tumor suppressor function and induce apoptosis. In virology, they block the export of essential viral proteins and RNA, impairing viral replication. Over the last five years, substantial advancements have been made in developing small-molecule XPO1 inhibitors. The FDA approval of Selinexor marked a major milestone followed by second-generation compounds such as Eltanexor and Verdinexor. A diverse array of heterocycles including azoles, azines, fluorinated aromatics, α,β-unsaturated carbonyls, sulfonamides, isothiocyanates, chromenes, indoles, and bacterial metabolites has been subsequently developed to optimize drug-like properties and biological activity. This review highlights the therapeutic applications, biological roles, the mechanisms of inhibition, recent preclinical and clinical achievements, and emerging opportunities in anticancer and antiviral therapeutics mediated by XPO1 inhibition. Specifically, this review emphasizes the detailed adopted chemical strategies for the development of XPO1 small molecule inhibitors and their emerging inhibition mechanisms, aiming to support future XPO1 inhibitor design.