Selinisol: a powerful inhibitor of XPO1

Selinexor (Selinexor), as an innovative drug, has attracted widespread attention in the field of tumor treatment due to its unique mechanism of action. It is an oral, slowly reversible, potent selective inhibitor of nuclear export (SINE) that specifically blocks the function of exportin 1 (XPO1). This unique mode of action allows selinesol to exhibit potential therapeutic effects in a variety of tumor types.

In mouse models of hematological and solid tumors, researchers found that selinesol significantly reduced tumor volume and improved survival at doses of 15-60 mg/m2 (equivalent to 5-20 g/kg). In addition, when selinesol is used in combination with other chemotherapy drugs or targeted therapy drugs, it can also produce significant synergy to further enhance the therapeutic effect.

In July 2019, the U.S. Food and Drug Administration (FDA) officially approved the combination of selinesol and dexamethasone for the accelerated treatment of adult patients with relapsed or refractory multiple myeloma (RRMM). These patients had disease that remained refractory to multiple drugs after at least four treatments, including at least two proteasome inhibitors, at least two immunomodulators, and an anti-CD38 monoclonal antibody.

XPO1 (also known as exportin-1) is overexpressed in multiple malignancies, including multiple myeloma and a variety of solid and liquid tumors. This overexpression is often associated with advanced stages of disease, resistance to treatment, and lower survival rates. The main function of XPO1 is to export tumor suppressor proteins and growth regulatory proteins from the nucleus to the cytoplasm. Furthermore, it is involved in regulating cytoplasmic localization and protein translation associated with key proto-oncogenes such as myc. More importantly, XPO1 is also involved in regulating the levels of glucocorticoid receptor (GR) in the nucleus.

Selinesol exerts its therapeutic effects by inhibitingXPO1 function. It blocks multiple mechanisms mediated by XPO1, thereby promoting apoptosis of malignant cells. After XPO1 is inhibited, normal cells undergo reversible cell cycle arrest and return to normal function after the drug effect is eliminated. Selinisol has good oral bioavailability with a half-life of approximately 6-8 hours. Following administration, pharmacokinetic and pharmacodynamic data showed increased induction of XPO1 mRNA and retention of tumor suppressor proteins (such as p53) in the nucleus, accompanied by increases in apoptotic markers. These data further confirm the potential and efficacy of selinesol as an XPO1 inhibitor in the treatment of tumors.

Therefore Seleniso is a speciesXPO1 inhibitor, and XPO1 is a nucleocytoplasmic transport protein involved in regulating the extranuclear transport of intracellular proteins. Selinisol shows therapeutic potential for multiple myeloma by inhibiting the function of XPO1 and interfering with the localization and function of abnormal proteins in cancer cells.