Xpovio

Selinexor is a reversible covalent selective inhibitor of nuclear export (SINE) compound that specifically blocks exportin 1 (XPO1). XPO1 is a major nuclear export protein that transports cargo proteins and several classes of messenger ribonucleic acid (mRNA) from the nucleus to the cytoplasm. XPO1 cargoes include many tumour suppressor proteins (TSPs), growth regulator proteins (GRPs) and mRNAs of growth promoting (oncogenic) proteins. XPO1 inhibition by selinexor leads to marked accumulation of TSPs and GRPs (such as tumor protein (p)53, p21, forkhead box transcription factor class O and IkappaB kinase in the nucleus (their site of action), and reduced expression of several oncoproteins (such as c myelocytomatosis, B lymphocytes (B cell) lymphoma 2 and cyclin D1) and translation/chaperon proteins (heat shock protein 70), resulting in cell cycle arrest and apoptosis of cancer cells. The combination of selinexor and dexamethasone or bortezomib demonstrated synergistic cytostatic and cytotoxic effects in multiple myeloma in vitro and in vivo models, including those resistant to proteasome inhibitors. Selinexor demonstrated pro apoptotic activity in vitro in multiple myeloma and diffuse large B cell lymphoma cell lines, in murine xenograft models as well as in patient tumour samples.