Identification

Name
Selinexor
Accession Number
DB11942
Description

Selinexor is a first-in-class selective inhibitor of nuclear transport (SINE) compound. It is currently approved for the treatment of multiple myeloma, a cancer which forms from antibody-producing plasma cells.6,7 This condition is typically treated with high dose bortezomib and dexamethasone chemotherapy followed by autologous stem-cell transplant. Other chemotherapies for multiple myeloma include lenalidomide and dexamethasone, thalidomide, and may include melphalan if the patient is not eligible for transplant.8 Selinexor was approved by the FDA in June 2019. It was granted fast track and orphan designation as well as accelerated approval based on single arm, open label trial data. The Bortezomib, Selinexor, and Dexamethasone in Patients With Multiple Myeloma (BOSTON) trial is planned to finish in 2020.9

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 443.313
Monoisotopic: 443.09292698
Chemical Formula
C17H11F6N7O
Synonyms
  • Selinexor
External IDs
  • KPT 330
  • KPT-330

Pharmacology

Indication

Selinexor is indicated for the treatment of relapsed or refractory multiple myeloma in combination with dexamethasone.Label Patients must have received at least 4 prior therapies and have disease which is refractory to least two proteasome inhibitors, at least two immunomodulatory agents, and an anti‐CD38 monoclonal antibody.

Associated Conditions
Contraindications & Blackbox Warnings
Learn about our commercial Contraindications & Blackbox Warnings data.
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Pharmacodynamics

Selinexor causes cell cycle arrest and apoptosis in cancer cells.Label

Mechanism of action

Selinexor binds to and inhibits exportin-1 (XPO1).Label XPO1 is a nuclear exporter protein which contains a pocket to which nuclear proteins can bind. When complexed with these proteins and Ran, activated through guanosine triphosphate (GTP) binding, the XPO1-protein-Ran-GTP complex is able to exit the nucleus through a nuclear pore. Once outside, GTP is hydrolyzed and the complex dissociates.4 The inhibition of this process in cancer cells allows the targets of XPO1, many of which are tumor suppressors, to collect in the nucleus and result in increased transcription of tumor suppressor genes. Tumor suppressor proteins known to be affected by XPO1 inhibition include p53, p73, adenomatous polyposis coli, retinoblastoma, forkhead box protein O, breast cancer 1, nucleophosmin, and merlin. Regulators of cell cycle progression are also affected, namely p21, p27, galectin-3, and Tob. Inhibitor of NFκB also collects in the nucleus as a result leading to reduced activity of NFκB, a known contributor to cancer.4,5 XPO1 participates in the formation of a complex with eukaryotic initiation factor 4E and contributes to the transport of messenger RNA for several oncegenes including cell cycle promotors, cyclin D1, cyclin E, and CDK2/4/6, as well as antiapoptotic proteins, Mcl-1 and Bcl-xL.4 These wide ranging changes in protein expression and gene transcription culminate in cell cycle arrest and the promotion of apoptosis in cancer cells.

TargetActionsOrganism
AExportin-1
inhibitor
Humans
Absorption

A single 80 mg dose of selinexor produces a mean Cmax of 680 ng/mL and a mean AUC of 5386 ng*h/mL.Label This relationship is dose proportion over the range of 3-85 mg/m2 which encompasses the range of 0.06-1.8 times the approved dosage. The official FDA labeling reports the Tmax as 4 hours but phase 1 studies have found a range of 2-4 hours.Label,1,2,3 Administering selinexor with food, either a high or low fat meal, results in an increase in the AUC of approximately 15-20% but this is not expected to be clinically significant.2

Volume of distribution

The mean apparent volume of distribution is 125 L.Label A phase 1 study reported mean apparent volumes of distribution ranging from 1.9-2.9 L/kg in their investigation of food and formulation effects.2

Protein binding

Selinexor is 95% bound to plasma proteins.Label

Metabolism

Selinexor is known to be metabolized through CYP3A4, UDP‐glucuronosyltransferases, and glutathione S-transferases although the metabolite profile has yet to be characterized in published literature.Label The primary metabolites found in urine and plasma are glucuronide conjugates.3

Route of elimination
Not Available
Half-life

Selinexor has a mean half-life of elimination of 6-8 hours.Label,1,2,3

Clearance

Selinexor has a mean apparent clearance of 17.9 L/h.Label

Adverse Effects
Learn about our commercial Adverse Effects data.
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Toxicity
Not Available
Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbametapirThe serum concentration of Selinexor can be increased when it is combined with Abametapir.
AmbrisentanThe excretion of Ambrisentan can be decreased when combined with Selinexor.
AtorvastatinThe excretion of Atorvastatin can be decreased when combined with Selinexor.
Bempedoic acidThe excretion of Bempedoic acid can be decreased when combined with Selinexor.
CaspofunginThe excretion of Caspofungin can be decreased when combined with Selinexor.
CenobamateThe serum concentration of Selinexor can be decreased when it is combined with Cenobamate.
CholecystokininThe excretion of Cholecystokinin can be decreased when combined with Selinexor.
Cholic AcidThe excretion of Cholic Acid can be decreased when combined with Selinexor.
CobimetinibThe excretion of Cobimetinib can be decreased when combined with Selinexor.
Conjugated estrogensThe excretion of Conjugated estrogens can be decreased when combined with Selinexor.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

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  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

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  • Action
    Action

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

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Food Interactions
  • Take with or without food. Co-administration with food does not affect pharmacokinetics.

Products

Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
XpovioTablet, film coated20 mg/1OralKaryopharm Therapeutics Inc.2019-07-10Not applicableUS flag
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories

ATC Codes
L01XX66 — Selinexor
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as phenyl-1,2,4-triazoles. These are organic compounds containing a 1,2,4-triazole substituted by a phenyl group.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Azoles
Sub Class
Triazoles
Direct Parent
Phenyl-1,2,4-triazoles
Alternative Parents
Trifluoromethylbenzenes / Pyrazines / Imidolactams / Vinylogous amides / Heteroaromatic compounds / Acrylic acids and derivatives / Carboxylic acid hydrazides / Azacyclic compounds / Organonitrogen compounds / Organofluorides
show 4 more
Substituents
Acrylic acid or derivatives / Alkyl fluoride / Alkyl halide / Aromatic heteromonocyclic compound / Azacycle / Benzenoid / Carbonyl group / Carboxylic acid derivative / Carboxylic acid hydrazide / Heteroaromatic compound
show 14 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Chemical Identifiers

UNII
31TZ62FO8F
CAS number
1393477-72-9
InChI Key
DEVSOMFAQLZNKR-RJRFIUFISA-N
InChI
InChI=1S/C17H11F6N7O/c18-16(19,20)11-5-10(6-12(7-11)17(21,22)23)15-26-9-30(29-15)4-1-14(31)28-27-13-8-24-2-3-25-13/h1-9H,(H,25,27)(H,28,31)/b4-1-
IUPAC Name
(2Z)-3-{3-[3,5-bis(trifluoromethyl)phenyl]-1H-1,2,4-triazol-1-yl}-N'-(pyrazin-2-yl)prop-2-enehydrazide
SMILES
FC(F)(F)C1=CC(=CC(=C1)C1=NN(\C=C/C(=O)NNC2=NC=CN=C2)C=N1)C(F)(F)F

References

General References
  1. Alexander TB, Lacayo NJ, Choi JK, Ribeiro RC, Pui CH, Rubnitz JE: Phase I Study of Selinexor, a Selective Inhibitor of Nuclear Export, in Combination With Fludarabine and Cytarabine, in Pediatric Relapsed or Refractory Acute Leukemia. J Clin Oncol. 2016 Dec;34(34):4094-4101. doi: 10.1200/JCO.2016.67.5066. Epub 2016 Oct 31. [PubMed:27507877]
  2. Gounder MM, Zer A, Tap WD, Salah S, Dickson MA, Gupta AA, Keohan ML, Loong HH, D'Angelo SP, Baker S, Condy M, Nyquist-Schultz K, Tanner L, Erinjeri JP, Jasmine FH, Friedlander S, Carlson R, Unger TJ, Saint-Martin JR, Rashal T, Ellis J, Kauffman M, Shacham S, Schwartz GK, Abdul Razak AR: Phase IB Study of Selinexor, a First-in-Class Inhibitor of Nuclear Export, in Patients With Advanced Refractory Bone or Soft Tissue Sarcoma. J Clin Oncol. 2016 Sep 10;34(26):3166-74. doi: 10.1200/JCO.2016.67.6346. Epub 2016 Jul 25. [PubMed:27458288]
  3. Abdul Razak AR, Mau-Soerensen M, Gabrail NY, Gerecitano JF, Shields AF, Unger TJ, Saint-Martin JR, Carlson R, Landesman Y, McCauley D, Rashal T, Lassen U, Kim R, Stayner LA, Mirza MR, Kauffman M, Shacham S, Mahipal A: First-in-Class, First-in-Human Phase I Study of Selinexor, a Selective Inhibitor of Nuclear Export, in Patients With Advanced Solid Tumors. J Clin Oncol. 2016 Dec;34(34):4142-4150. doi: 10.1200/JCO.2015.65.3949. Epub 2016 Oct 31. [PubMed:26926685]
  4. Gandhi UH, Senapedis W, Baloglu E, Unger TJ, Chari A, Vogl D, Cornell RF: Clinical Implications of Targeting XPO1-mediated Nuclear Export in Multiple Myeloma. Clin Lymphoma Myeloma Leuk. 2018 May;18(5):335-345. doi: 10.1016/j.clml.2018.03.003. Epub 2018 Mar 14. [PubMed:29610030]
  5. Xia Y, Shen S, Verma IM: NF-kappaB, an active player in human cancers. Cancer Immunol Res. 2014 Sep;2(9):823-30. doi: 10.1158/2326-6066.CIR-14-0112. [PubMed:25187272]
  6. Xpovio FDA Announcement [Link]
  7. Cancer.ca: Multiple Myeloma [Link]
  8. BC Cancer Agency: Treatment of Multiple Myeloma [Link]
  9. Clinical Trials: BOSTON Trial [Link]
  10. ChemSpider: Selinexor [Link]
  11. FDA Approved Drug Products: Xpovio oral tablets [Link]
PubChem Compound
71481097
PubChem Substance
347828269
ChemSpider
32701989
RxNav
2178390
ChEMBL
CHEMBL3545185
ZINC
ZINC000096170454
Wikipedia
Selinexor
FDA label
Download (588 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentMultiple Myeloma (MM)1
3Not Yet RecruitingTreatmentMalignancies / Novel Coronavirus Infectious Disease (COVID-19) / Respiratory Viral Infections1
3RecruitingTreatmentEndometrial Cancer1
2Active Not RecruitingTreatmentDiffuse Large B-Cell Lymphoma (DLBCL)1
2Active Not RecruitingTreatmentMyelodysplastic Syndromes (MDS)1
2CompletedTreatmentAcute Myeloid Leukemia (AML)1
2CompletedTreatmentAcute Myeloid Leukemia (Relapsed/Refractory)1
2CompletedTreatmentBreast Cancer1
2CompletedTreatmentBreast Cancer / Cervical Carcinoma / Endometrial Carcinoma / Ovarian Carcinoma1
2CompletedTreatmentGlioblastomas / Gliomas1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Tablet, film coatedOral20 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US9079865No2015-07-142032-07-26US flag
US9714226No2017-07-252032-07-26US flag
US8999996No2015-04-072032-09-15US flag
US10519139No2019-12-312035-08-14US flag
US10544108No2012-07-262032-07-26US flag
Additional Data Available
  • Filed On
    Filed On

    The date on which a patent was filed with the relevant government.

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Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubility20mg/mLChemSpider: Selinexor
Predicted Properties
PropertyValueSource
Water Solubility0.00555 mg/mLALOGPS
logP2.85ALOGPS
logP3.07ChemAxon
logS-4.9ALOGPS
pKa (Strongest Acidic)12.18ChemAxon
pKa (Strongest Basic)1.34ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area97.62 Å2ChemAxon
Rotatable Bond Count7ChemAxon
Refractivity120 m3·mol-1ChemAxon
Polarizability35.61 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Mediates the nuclear export of cellular proteins (cargos) bearing a leucine-rich nuclear export signal (NES) and of RNAs. In the nucleus, in association with RANBP3, binds cooperatively to the NES on its target protein and to the GTPase RAN in its active GTP-bound form (Ran-GTP). Docking of this complex to the nuclear pore complex (NPC) is mediated through binding to nucleoporins. Upon transit of a nuclear export complex into the cytoplasm, disassembling of the complex and hydrolysis of Ran-GTP to Ran-GDP (induced by RANBP1 and RANGAP1, respectively) cause release of the cargo from the export receptor. The directionality of nuclear export is thought to be conferred by an asymmetric distribution of the GTP- and GDP-bound forms of Ran between the cytoplasm and nucleus. Involved in U3 snoRNA transport from Cajal bodies to nucleoli. Binds to late precursor U3 snoRNA bearing a TMG cap.
Specific Function
Nuclear export signal receptor activity
Gene Name
XPO1
Uniprot ID
O14980
Uniprot Name
Exportin-1
Molecular Weight
123384.98 Da

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent uptake of organic anions such as 17-beta-glucuronosyl estradiol, taurocholate, triiodothyronine (T3), leukotriene C4, dehydroepiandrosterone sulfate (DHEAS), methotre...
Gene Name
SLCO1B3
Uniprot ID
Q9NPD5
Uniprot Name
Solute carrier organic anion transporter family member 1B3
Molecular Weight
77402.175 Da

Drug created on October 20, 2016 15:03 / Updated on June 12, 2020 11:42

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