Is selinesol an xpo1 inhibitor?

Selinexor (Selinexor) is an XPO1 inhibitor. Selinisol is an oral, first-in-class, slowly reversible, potent selective inhibitor of nuclear export (SINE) compound that specifically blocks exportin 1 (XPO1), a mechanism of action applicable to a variety of tumor types. In mouse models of hematological and solid tumors, tumor reduction and increased survival were observed at doses of selinesol 15-60 mg/m2 (5-20 g/kg). Furthermore, significant synergistic effects were observed when selinesol was combined with various chemotherapy and targeted therapies.

On July 3, 2019, the U.S. Food and Drug Administration (FDA) granted accelerated approval to selinesol in combination with dexamethasone for adult patients with relapsed or refractory multiple myeloma (RRMM) who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, at least two immunomodulators, and an anti-CD38 monoclonal antibody.

exportin-1 (xpo1) is overexpressed in a variety of malignancies, including multiple myeloma, and in a variety of solid and liquid tumors. XPO1 expression is often associated with advanced disease, resistance to treatment, and poor survival. XPO1 exports tumor suppressor and growth regulatory proteins out of the nucleus. XPO1 also regulates cytoplasmic localization, which in turn regulates the translation of a key proto-oncogene (i.e., myc) in complex with the cargo protein eukaryotic initiation factor 4E (eIF4E). Furthermore, XPO1 is involved in regulating nuclear levels of glucocorticoid receptor (GR).

Selinesol inhibitsXPO1 by blocking each of the above XPO1-mediated mechanisms to promote apoptosis of malignant cells. After XPO1 inhibition, normal cells undergo reversible cell cycle arrest and recover upon removal of the block. Selinisol is orally bioavailable with a half-life (T) of approximately 6-8 hours. Following administration, pharmacokinetic (PK) and pharmacodynamic (PD) data showed induction of XPO1 mRNA and nuclear retention of tumor suppressor proteins such as p53, accompanied by increases in apoptotic markers.