Selective Inhibitors of Nuclear Export (SINE) drugs

Selective inhibitors of nuclear export use a new strategy for stopping cancer growth by increasing the amount of naturally occurring tumor suppressors in the cells.  While only one such drug has made it to clinical use, the idea is so intriguing that scientists are still interested in this path to fighting cancer.

In the normal life of a healthy cell, proteins are transferred from where they are made to elsewhere.  Some proteins are made inside the nucleus and must get through the membrane that encloses the nucleus to the larger cell.  Special proteins called export proteins (exportins) help facilitate the passage of these proteins.  A key one of these transport proteins is exportin-1 (XPO1), also known as chromosomal region maintenance 1 (CRM1) which helps transport over 200 different proteins including tumor suppressor (TSP) and growth regulatory (GRP) proteins.  In normal healthy cells this export is a good thing and prevents these proteins from building up in the nucleus.  In cancer cells, however, we would prefer the tumor suppressors not be exported.  And the cancerous cells often have higher than normal levels of XPO1 – this has been found in both blood and solid tumor cancers.

Scientists have found compounds that are selective inhibitors of nuclear export (SINE). These can block the export of TSPs and GRPs and may be effective anti-cancer drugs.  Selinexor – code named KPT-330 – was an early drug candidate and the only one that has progressed through clinical trials and shown enough efficacy that the FDA approved it under accelerated approval in 2019.

Because SINE is a new type of therapy, regulators are cautious.  The approval of Selinexor came with the restriction that the labelling be very tight.  Selinexor was approved for use against multiple myeloma that had relapsed and was proving intractable to other treatments.  The new drug is supposed to be administered in combination with dexamethasone (a widely used steroid drug), and it is only supposed to be used if that patient has already been treated with two proteasome inhibitors (there only three proteasome inhibitors approved for cancer), and if they have been treated with two immunomodulatory agents, one of which must be an anti-CD38 monoclonal antibody.  So the agency approved it mostly if patients were out of other options.

elderly chemotherapy patientBut this type of restricted approval is common for first-in-class medications.  As doctors in the clinic gain more experience and data comes in, use in other diseases and indications can be approved.  In 2020 the FDA expanded approval to patients with  diffuse large B-cell lymphoma, when those patients had already been through two other treatments. 

Could the drug be approved for more diseases?  Clinical trials are underway to see if it works on endometrial cancer and advanced liposarcoma.

SINE agents attracted a lot of research interest in the mid-2010s but enthusiasm has only produced one commercially available drug.  Research continues but we are unaware of other SINE agents in clinical trials.  Other compounds that were researched in at least the lab include verdinexor (KPT-335), KPT-185, KPT-276, and KPT-251.

SINE compounds have also attracted the interest of anti-aging researchers.


Brand/Trade Names: Xpovio

Manufacturer: Karyopharm Therapeutics

Formula: C17H11F6N7O

Mechanism: SINE

Manufacturer: Karyopharm. Website.

Administration: Oral

Notes: First approved by the FDA in 2019.   Approved for treatment of multiple myeloma and diffuse large B-cell lymphoma.