Selinexor

Identification

Brand Names

Xpovio 100 Mg Once Weekly Carton

Generic Name

Selinexor

DrugBank Accession Number

DB11942

Background

Selinexor is a first-in-class selective inhibitor of nuclear transport (SINE) compound. Selinexor, in combination with bortezomib and dexamethasone, is currently approved for the treatment of multiple myeloma, a type of cancer formed from antibody-producing plasma cells.^6,7,11 This condition is typically treated with high dose bortezomib and dexamethasone chemotherapy followed by an 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 also granted accelerated approval for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) that have gone through at least 2 lines of systemic therapy.¹¹

The FDA approved Selinexor in June 2019.¹¹ The use of selinexor in combination with bortezomib and dexamethasone was approved by Health Canada in June 2022 for the treatment of multiple myeloma in adult patients who have received at least one prior therapy.

Type

Small Molecule

Groups

Approved, Investigational

Structure

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Selinexor (DB11942)

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Weight

Average: 443.313
Monoisotopic: 443.09292698

Chemical Formula

C₁₇H₁₁F₆N₇O

Synonyms

• Selinexor

External IDs

• KPT 330
• KPT-330

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Pharmacology

Indication

Selinexor is indicated in combination with bortezomib and dexamethasone for the treatment of multiple myeloma in adult patients who have received at least one prior therapy. Selinexor is also indicated in combination with dexamethasone for the treatment of relapsed or refractory multiple myeloma in adult patients who have received at least four prior therapies and who are refractory to at least two proteasome inhibitors, two immunomodulatory agents, and an anti-CD38 monoclonal antibody.¹¹

Selinexor is also indicated under an accelerated approval scheme for the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified, including that arising from follicular lymphoma, in adult patients who have received at least two prior lines of systemic therapy. Continued approval for this indication may be contingent on verification in confirmatory clinical trials.¹¹

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Used in combination to treat	Multiple myeloma (mm)	Regimen in combination with: Dexamethasone (DB01234), Bortezomib (DB00188)	••••••••••••	•••••	•• ••••• ••• ••••• •••••••	••••••
Used in combination to treat	Refractory multiple myeloma	Regimen in combination with: Dexamethasone (DB01234)	••••••••••••	•••••	•• ••••• • ••••• ••••••••• •••••••••• •••••••••• •• •• ••••• ••• •••••••••• ••••••••••• •• ••••• ••• •••••••••••••••• ••••••• ••• •• ••••••••• •••••••••• ••••••••	••••••
Used in combination to treat	Relapsed multiple myeloma	Regimen in combination with: Dexamethasone (DB01234)	••••••••••••	•••••	•••••••••• •• •• ••••• ••• •••••••••• ••••••••••• •• ••••• ••• •••••••••••••••• ••••••• ••• •• ••••••••• •••••••••• ••••••••• •• ••••• • ••••• ••••••••• •••••••••	••••••
Treatment of	Refractory diffuse large b-cell lymphoma nos		••••••••••••	•••••	•• ••••• ••• ••••• •••••••• •••••••••	••••••
Treatment of	Relapsed diffuse large b-cell lymphoma nos		••••••••••••	•••••	•• ••••• ••• ••••• •••••••• •••••••••	••••••

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Pharmacodynamics

Selinexor causes cell cycle arrest and apoptosis in cancer cells.¹¹

Mechanism of action

Selinexor binds to and inhibits exportin-1 (XPO1).¹¹ 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.

Target	Actions	Organism
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

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Toxicity

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.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Abametapir	The serum concentration of Selinexor can be increased when it is combined with Abametapir.
Ambrisentan	The excretion of Ambrisentan can be decreased when combined with Selinexor.
Ambroxol	The risk or severity of methemoglobinemia can be increased when Selinexor is combined with Ambroxol.
Amiodarone	The metabolism of Selinexor can be decreased when combined with Amiodarone.
Amprenavir	The metabolism of Selinexor can be decreased when combined with Amprenavir.

Food Interactions

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

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Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Nexpovio	Tablet, film coated	20 mg	Oral	Stemline Therapeutics B.V.	2021-06-01	Not applicable
Nexpovio	Tablet, film coated	20 mg	Oral	Stemline Therapeutics B.V.	2021-06-01	Not applicable
Nexpovio	Tablet, film coated	20 mg	Oral	Stemline Therapeutics B.V.	2021-06-01	Not applicable
Nexpovio	Tablet, film coated	20 mg	Oral	Stemline Therapeutics B.V.	2023-03-15	Not applicable
Nexpovio	Tablet, film coated	20 mg	Oral	Stemline Therapeutics B.V.	2021-06-01	Not applicable

Categories

ATC Codes

L01XX66 — Selinexor

• L01XX — Other antineoplastic agents
• L01X — OTHER ANTINEOPLASTIC AGENTS
• L01 — ANTINEOPLASTIC AGENTS
• L — ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS

Drug Categories

• Antineoplastic Agents
• Antineoplastic and Immunomodulating Agents
• Cytochrome P-450 CYP3A Substrates
• Cytochrome P-450 CYP3A4 Substrates
• Cytochrome P-450 Substrates
• Nuclear Export Inhibitors
• OATP1B3 inhibitors

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 / Organic oxides / Hydrocarbon derivatives / Carbonyl compounds / Alkyl fluorides

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Substituents

Acrylic acid or derivatives / Alkyl fluoride / Alkyl halide / Aromatic heteromonocyclic compound / Azacycle / Benzenoid / Carbonyl group / Carboxylic acid derivative / Carboxylic acid hydrazide / Heteroaromatic compound / Hydrocarbon derivative / Imidolactam / Monocyclic benzene moiety / Organic nitrogen compound / Organic oxide / Organic oxygen compound / Organofluoride / Organohalogen compound / Organonitrogen compound / Organooxygen compound / Phenyl-1,2,4-triazole / Pyrazine / Trifluoromethylbenzene / Vinylogous amide

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Molecular Framework

Aromatic heteromonocyclic compounds

External Descriptors

Not Available

Affected organisms

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. [Article]
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. [Article]
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. [Article]
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. [Article]
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. [Article]
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 (selinexor) oral tablets [Link]
12. Health Canada Approved Drug Products: XPOVIO (selinexor) oral tablets [Link]

External Links

PubChem Compound

71481097

PubChem Substance

347828269

ChemSpider

32701989

BindingDB

50527778

RxNav

2178390

ChEMBL

CHEMBL3545185

ZINC

ZINC000096170454

Wikipedia

Selinexor

FDA label

Download (588 KB)

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
4	Recruiting	Treatment	Diffuse Large B-Cell Lymphoma, Not Otherwise Specified	1
3	Active Not Recruiting	Treatment	Endometrial Cancer	1
3	Active Not Recruiting	Treatment	Multiple Myeloma (MM)	1
3	Active Not Recruiting	Treatment	Relapsed/Refractory Multiple Myeloma (RRMM)	1
3	Completed	Treatment	Cancer / Coronavirus Disease 2019 (COVID‑19) / Viral Respiratory Tract Infection	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Tablet, film coated	Oral	20 MG
Tablet	Oral	20 mg
Tablet, film coated	Oral	20 mg/1
Tablet, film coated	Oral	40 mg/1
Tablet, film coated	Oral	50 mg/1
Tablet, film coated	Oral	60 mg/1

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US9079865	No	2015-07-14	2032-07-26
US9714226	No	2017-07-25	2032-07-26
US8999996	No	2015-04-07	2032-09-15
US10519139	No	2019-12-31	2035-08-14
US10544108	No	2020-01-28	2032-07-26
US11034660	No	2021-06-15	2032-07-26
US11753401	No	2015-08-14	2035-08-14
US11746102	No	2015-08-14	2035-08-14
US11787771	No	2012-07-26	2032-07-26
US11807629	No	2015-08-14	2035-08-14

Properties

State

Solid

Experimental Properties

Property	Value	Source
water solubility	20mg/mL	ChemSpider: Selinexor

Predicted Properties

Property	Value	Source
Water Solubility	0.00555 mg/mL	ALOGPS
logP	2.85	ALOGPS
logP	3.07	Chemaxon
logS	-4.9	ALOGPS
pKa (Strongest Acidic)	12.18	Chemaxon
pKa (Strongest Basic)	1.34	Chemaxon
Physiological Charge	0	Chemaxon
Hydrogen Acceptor Count	6	Chemaxon
Hydrogen Donor Count	2	Chemaxon
Polar Surface Area	97.62 Å2	Chemaxon
Rotatable Bond Count	7	Chemaxon
Refractivity	120 m3·mol-1	Chemaxon
Polarizability	35.61 Å3	Chemaxon
Number of Rings	3	Chemaxon
Bioavailability	1	Chemaxon
Rule of Five	Yes	Chemaxon
Ghose Filter	Yes	Chemaxon
Veber's Rule	No	Chemaxon
MDDR-like Rule	Yes	Chemaxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0006-0002900000-8e23a1394d55353e6660
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	splash10-00dr-0005900000-1069fe3aa637e33b7045
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	splash10-004r-6902200000-a2b99db1794901725c80
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	splash10-05mo-0269100000-c462a8d9ccd104ef3156
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	splash10-053r-0019000000-22001ab8c6a27194f087
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	splash10-000f-7193000000-736af70485761a88ead0
Predicted 1H NMR Spectrum	1D NMR	Not Applicable
Predicted 13C NMR Spectrum	1D NMR	Not Applicable

Chromatographic Properties

Collision Cross Sections (CCS)

Adduct	CCS Value (Å2)	Source type	Source
[M-H]-	187.09317	predicted	DeepCCS 1.0 (2019)
[M+H]+	189.48874	predicted	DeepCCS 1.0 (2019)
[M+Na]+	195.40126	predicted	DeepCCS 1.0 (2019)

Targets

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Details1. Exportin-1

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

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Drug created at October 20, 2016 21:03 / Updated at December 01, 2022 11:27