**2. Selinexor-a small molecule exportin 1 inhibitor**

The structural formula of selinexor is shown in **Figure 2**. Selinexor is a first member of small molecule oral inhibitors of exportin 1 developed for the treatment of cancer. Selinexor in combination with a synthetic glucocorticoid dexamethasone was approved by the FDA (U.S. Food and Drug Administration) on July 3, 2019 for the treatment of adult patients with relapsed or refractory multiple myeloma (RRMM) who have received at least four prior therapies. Selinexor synergizes with dexamethasone and inhibits the mTOR pathway and subsequently induces cell death in multiple myeloma cells [19]. Selinexor increases the expression of glucocorticoid receptor and in combination with dexamethasone stimulates transcriptional activity of the glucocoticoid receptor [19]. Selinexor is studied in clinical trials also in many hematological and solid cancers [20–24]. The treatment with selinexor in preclinical and clinical studies resulted in nuclear localization of tumor suppressor proteins (eg p53 and FOXO3A), induced apoptosis and decreased proliferation. Selinexor reduces the expression of DNA damage repair proteins and sensitizes cancer cells to DNA damaging agents [25]. Selinexor blocks the transcription factor NF-κB and induces ribosomal stressby disruption of ribosomal subunits assembly [26].

Selinexor is orally bioavailable with a mean half-life 6–8 h after a single dose. Selinexor pharmacokinetics are not significantly affected by age, sex, ethnicity, renal impairment or mild hepatic impairment. Most frequent adverse events associated with selinexor treatment are thrombocytopenia, fatigue, nausea, anemia, decreased appetite, decreased weight, diarrhoea, vomiting, hyponatremia, neutropenia, leukopenia, constipation, dyspnoea, and upper respiratory tract infection.

#### **Figure 2.**

*Multiple Myeloma*

**2**

**Figure 1.**

binding to cysteine 528 (Cys528) in the cargo proteins NES-binding pocket of exportin1 and contribute to cancer cell death [15]. All these drugs have been devel-

*Exportin 1-mediated nuclear export in multiple myeloma; Abbreviations: Ran-GDP and Ran-GTP – GDP or GTP bound Ras related factor; NPC – nuclear pore complex; SINE - selective inhibitor of nuclear export; FOXO – a subgroup of the Forkhead family of transcription factors, p53 – a tumor suppressor protein and transcription factor; XPO1 – exportin 1, also known as chromosomal maintenance 1 (CRM1); (A) XPO1 transports nuclear proteins out of the nucleus. Cargo proteins such as FOXO or p53 that are marked for export from the nucleus bind a pocket in XPO1 in the presence of the activated small G-protein, Ran. The active Ran-GTP-XPO1-cargo complex is exported from the nucleus through the nuclear pore complex driven by the concentration gradient of Ran-GTP across the nuclear membrane. Once in the cytoplasm, Ran-GTP is hydrolyzed to Ran-GDP, and the XPO1-cargo complex dissociates. (B) SINE compounds (Hexagons) bind to XPO1-Cys528 and occupy the cargo-binding pocket of XPO1 and prevent formation of the Ran-GTP-XPO1-cargo complex. The result is increased nuclear localization of tumor* 

oped by Karyopharm Therapeutics Inc., Natick, MA.

*suppressor cargo proteins and upregulation of their transcriptional activity [15].*

*Chemical structure of selinexor (alternative names: ATG-010, KPT-330, ONO7705, XPOVIO, CRM1 nuclear export inhibitor). Chemical name: (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl-1H-1,2,4-triazol-1-yl)-N´- (pyrazin-2-yl)acrylohydrazide.*
