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Synonyms: compound 70 [WO2013019561A1] | KPT-330 | KPT330 | Nexpovio® | Xpovio®
selinexor is an approved drug (FDA (2019), EMA (2021))
Compound class:
Synthetic organic
Comment: Selinexor (KPT-330) is an inhibitor of the nuclear export protein XPO1 (a.k.a. exportin 1) that is being developed as an anti-neoplastic agent by Karyopharm Therapeutics. It is a first-in-class inhibitor that exploits a novel mechanism of action compared to existing chemotherapeutics [2,7-8]. The chemical structure is claimed in patent WO2013019561A1 (as compound 70) [9].
Ligand Activity Visualisation ChartsThese are box plot that provide a unique visualisation, summarising all the activity data for a ligand taken from ChEMBL and GtoPdb across multiple targets and species. Click on a plot to see the median, interquartile range, low and high data points. A value of zero indicates that no data are available. A separate chart is created for each target, and where possible the algorithm tries to merge ChEMBL and GtoPdb targets by matching them on name and UniProt accession, for each available species. However, please note that inconsistency in naming of targets may lead to data for the same target being reported across multiple charts. ✖ |
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Summary of Clinical Use  |
| The first FDA approval of selinexor (KPT-330) was granted in July 2019, as a treatment for relapsed/refractory multiple myeloma in patients who have received at least four prior therapies (refractory to ≥two proteasome inhibitors, ≥two immunomodulatory agents, and an anti-CD38 monoclonal antibody). Clinical trials in additional cancers are ongoing. EMA approval for the treatment of MM was issued in March 2021. Click here to view the full list of KPT-330 studies at ClinicalTrials.gov. The most advance trials are Phase 3 studies in endometrial cancer (NCT03555422) and dedifferentiated (advanced) liposarcoma (NCT02606461). In June 2020, the FDA granted accelerated approval for the use of selnexor for relapsed/refractory diffuse large B-cell lymphoma (DLBCL, including that arising from follicular lymphoma) after at least 2 lines of systemic therapy. Because of its novel mechanism of action selinexor is an ideal candidate for use in combination with (or following failure of) other chemotherapeutics such as proteasome inhibitors, kinase inhibitors and checkpoint inhibitors [1,4]. It has also been discovered that treatment with selinexor can re-sensitize cancer cells to previous treatments to which they had become refractory [6]. Repurposing for COVID-19: SINE compounds like selinexor have been shown to disrupt the replication of multiple viruses in vitro and in vivo and to mediate anti-inflammatory and anti-viral effects in animal models [10]. In respect of SARS-CoV-2, SINE compounds have been reported to exhibit potential to interfere with interactions between viral proteins and key host proteins [3]. Based on this in vitro observation, low-dose selinexor has been advanced to Phase 2 investigation in patients with severe COVID-19 (NCT04349098). |
| Mechanism Of Action and Pharmacodynamic Effects |
| XPO1 facilitates the nuclear export of cargo proteins that carry a leucine-rich nuclear export signal [5]. These cargo proteins include ribosomal subunits and a number of tumour suppressor proteins and oncoproteins. Certain cancer cells overexpress XPO1 in order to shuttle tumour suppressor proteins out of the nucleus as a mechanism to escape their apoptosis-inducing effects. Pharmacological inhibition of XPO1 sequesters the tumour suppressor proteins in the nucleus where they can resume normal function and promote apoptosis of the tumour cells. Normal cells are insensitive to the effects of XPO1 inhibition. |
