By inhibiting the XPO1 protein, SINEs lead to a buildup of tumor suppressors in the nucleus of malignant cells and reduce levels of oncogene products which drive cell proliferation. This ultimately leads to cell cycle arrest and death of cancer cells by apoptosis. In vitro, this effect appeared to spare normal (non-malignant) cells.Inhibiting XPO1 affects many different cells in the body which may explain the incidence of adverse reactions to selinexor. Thrombocytopenia, for example, is a mechanistic and dose-dependent effect, occurring because selinexor causes a buildup of the transcription factor STAT3 in the nucleus of hematopoietic stem cells, preventing their differentiation into mature megakaryocytes (platelet-producing cells) and thus slowing production of new platelets. Chemistry
Selinexor is a fully synthetic small-molecule compound, developed by means of a structure-based drug design process known as induced-fit docking. It binds to a cysteine residue in the nuclear export signal groove of exportin 1. Although this bond is covalent, it is slowly reversible. History
Selinexor was developed by Karyopharm Therapeutics, a pharmaceutical company focused on the development of drugs that target nuclear transport. It was approved in the United States in July 2019, on the basis of a single-arm Phase IIb clinical trial. The FDA decided to grant accelerated approval despite a previous recommendation from an FDA Advisory Committee Panel which had voted 8–5 to delay approving the drug until the results from an ongoing Phase III study were known.Selinexor in combination with dexamethasone was granted accelerated approval and was granted orphan drug designation.
In this phase 2 randomized placebo-controlled single-blind trial named XPORT-CoV-1001 with a total of 190 participants with severe COVID-19, treatment with selinexor resulted in higher mortality (16% vs. 9%) and more serious adverse events (23% vs. 16%) than placebo. References
External links
"Selinexor". Drug Information Portal. U.S. National Library of Medicine.