The unique mechanism of selinesol against myelofibrosis revealed

Selinexor (Selinexor), as an innovative oral nuclear export inhibitor (SINE), can treat multiple myeloma (MM). The mechanism of action of selinesol is unique and complex. It binds reversibly and selectively to cysteine u200bu200b528, in the cargo binding pocket of XPO1, thereby effectively disabling the nuclear export function of XPO1. This process triggers multiple anti-tumor effects:

1. Selinesol can inhibit the nuclear export of tumor suppressor protein (TSP), causing it to accumulate in the nucleus and lose its function, thereby triggering the apoptosis program of tumor cells.

2. Selinesol also interferes with the nuclear export process of oncoproteinmRNA. Normally, EIF4E serves as a "cargo" of XPO1, responsible for carrying specific oncoprotein mRNAs (such as cyclin D1, B-cell lymphoma 2, c-myc, etc.) to the cytoplasm for translation. However, selinesol is able to block this transport process, causing these oncoprotein mRNAs to be trapped in the nucleus, thereby greatly reducing the synthesis rate of oncoproteins in the cytoplasm.

3.The synergistic effect of selinesol and dexamethasone is also an important part of its anti-cancer mechanism. When used in combination, selinesol can significantly enhance the transcriptional and translational activities of the glucocorticoid receptor (GR), thereby amplifying the anti-tumor effect and inducing tumor cell death.

4. Selinesol also reduces osteoclast production and bone resorption activity by directly inhibitingRANKL-induced nuclear factor kappa B (NF-κB) and nuclear factor of activated T cell c1 (NFATc1), while this process has minimal impact on osteoblasts and bone marrow stromal cells.

This unique mechanism of action allows selinesol to excel in selective cytotoxicity against tumor cells. By inhibiting the nuclear export function ofXPO1, selinesol can accurately induce the death of malignant cells while maximally protecting normal cells from damage. This treatment strategy undoubtedly provides new hope for patients with multiple myeloma.