Selinexor

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Selinexor
Skeletal formula of selinexor
Clinical data
Trade namesXpovio
Pregnancy
category
  • Known to cause fetal harm
Routes of
administration
Oral
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding95%
MetabolismHepatic oxidation, glucuronidation, and conjugation, by CYP3A4, UGT and GST
Elimination half-life6–8 h
Identifiers
CAS Number
PubChem CID
DrugBank
UNII
Chemical and physical data
FormulaC17H11F6N7O
Molar mass443.313 g·mol−1
3D model (JSmol)

Selinexor (INN, trade name Xpovio; codenamed KPT-330) is a selective inhibitor of nuclear export used as an anti-cancer drug. It works by quasi-irreversibly binding to exportin 1 and thus blocking the transport of several proteins involved in cancer-cell growth from the cell nucleus to the cytoplasm, which ultimately arrests the cell cycle and leads to apoptosis.[1] It is the first drug with this mechanism of action.[2][3]

Selinexor was granted accelerated approval by the U.S. Food and Drug Administration in July 2019, for use as a drug of last resort in people with multiple myeloma. In clinical trials, it was associated with a high incidence of severe side effects, including low platelet counts and low blood sodium levels.[3][4]

Medical uses[edit]

Selinexor is restricted for use in combination with the steroid dexamethasone in people with relapsed or refractory multiple myeloma which has failed to respond to at least four or five other therapies (so-called "quad-refractory" or "penta-refractory" myeloma),[5] for whom no other treatment options are available.[3][4] It is the first drug to be approved for this indication.[6]

Adverse effects[edit]

In the clinical study used to support FDA approval, selinexor was associated with high rates of pancytopenia, including leukopenia (28%), neutropenia (34%, severe in 21%), thrombocytopenia (74%, severe in 61% of patients), and anemia (59%).[4][7] The most common non-hematological side effects were gastrointestinal reactions (nausea, anorexia, vomiting, and diarrhea), hyponatremia (low blood sodium levels, occurring in up to 40% of patients), and fatigue.[7][8] More than half of all patients who received the drug developed infections, including fatal cases of sepsis.[7] However, these data are from an open-label trial, and thus cannot be compared to placebo or directly attributed to treatment.

Mechanism of action[edit]

Schematic illustration of the Ran cycle of nuclear transport. Selinexor inhibits this process at the nuclear export receptor (upper right).

Like other so-called selective inhibitors of nuclear export (SINEs), selinexor works by binding to exportin 1 (also known as CRM1). CRM1 is a karyopherin which performs nuclear transport of several proteins, including tumor suppressors, oncogenes, and proteins involved in governing cell growth, from the cell nucleus to the cytoplasm; it is often overexpressed and its function misregulated in several types of cancer.[1] By restoring nuclear transport of these proteins to normal, SINEs lead to a buildup of tumor suppressors in the nucleus of malignant cells and reduce levels of oncogene products which drive cell proliferation. This ultimately leads to cell cycle arrest and death of cancer cells by apoptosis.[1][2][7] In vitro, this effect appeared to spare normal (non-malignant) cells.[1][8]

Because CRM1 is a pleiotropic gene, inhibiting it affects many different systems in the body, which explains the high incidence of adverse reactions to selinexor.[2] Thrombocytopenia, for example, is a mechanistic and dose-dependent effect, occurring because selinexor causes a buildup of the transcription factor STAT3 in the nucleus of hematopoietic stem cells, preventing their differentiation into mature megakaryocytes (platelet-producing cells) and thus slowing production of new platelets.[2]

Chemistry[edit]

Selinexor is a fully synthetic small-molecule compound, developed by means of a structure-based drug design process known as induced-fit docking. It binds to a cysteine residue in the nuclear export signal groove of exportin 1. Although this bond is covalent, it is not irreversible.[1]

History[edit]

Selinexor was developed by Karyopharm Therapeutics of Newton, Massachusetts, a pharmaceutical company devoted entirely to the development of drugs that target nuclear transport. It was approved by the FDA on July 3, 2019, on the basis of a single uncontrolled clinical trial. The decision was controversial, and overruled the previous recommendation of an independent advisory panel which had voted 8–5 against approving the drug, due to concerns about efficacy and toxicity.[3]

Research[edit]

Under the codename KPT-330, selinexor was tested in several preclinical animal models of cancer, including pancreatic cancer, breast cancer, non-small-cell lung cancer, lymphomas, and acute and chronic leukemias.[9] In humans, early clinical trials (phase I) have been conducted in non-Hodgkin lymphoma, blast crisis, and a wide range of advanced or refractory solid tumors, including colon cancer, head and neck cancer, melanoma, ovarian cancer, and prostate cancer.[9] Compassionate use in patients with acute myeloid leukemia has also been reported.[9]

The pivotal clinical trial which served to support approval of selinexor for people with relapsed/refractory multiple myeloma was an open-label study of 122 patients known as the STORM trial.[7] In all of the enrolled patients, selinexor was used as fifth-line or sixth-line therapy after conventional chemotherapy, targeted therapy with bortezomib, carfilzomib, lenalidomide, pomalidomide, and a monoclonal antibody (daratumumab or isatuximab);[5] nearly all had also undergone hematopoietic stem cell transplantation to no effect.[7] The overall response rate was 25%, and no patients had a complete response.[7] However, the response rate was higher in patients with high-risk myeloma (cytogenetic abnormalities associated with a worse prognosis).[5] The median time to progression was 2.3 months overall and 5 months in patients who responded to the drug.[2]

As of 2019, phase I/II and III trials are ongoing,[3][9] including the use of selinexor in other cancers and in combinations with other drugs used for multiple myeloma.[2]

References[edit]

  1. ^ a b c d e Fung HY, Chook YM (2014). "Atomic basis of CRM1-cargo recognition, release and inhibition". Semin Cancer Biol. 27: 52–61. doi:10.1016/j.semcancer.2014.03.002. PMC 4108548. PMID 24631835.
  2. ^ a b c d e f Gandhi UH, Senapedis W, Baloglu E, Unger TJ, Chari A, Vogl D; et al. (2018). "Clinical implications of targeting XPO1-mediated nuclear export in multiple myeloma". Clin Lymphoma Myeloma Leuk. 18 (5): 335–345. doi:10.1016/j.clml.2018.03.003. PMID 29610030.CS1 maint: multiple names: authors list (link)
  3. ^ a b c d e Feuerstein, Adam (2019-07-03). "FDA approves new multiple myeloma drug despite toxicity concerns". STAT. Retrieved 2019-07-06.
  4. ^ a b c Mulcahy, Nick (2019-07-03). "FDA Approves Selinexor for Refractory Multiple Myeloma". Medscape. Retrieved 2019-07-06.
  5. ^ a b c Chim CS, Kumar SK, Orlowski RZ, Cook G, Richardson PG, Gertz MA; et al. (2018). "Management of relapsed and refractory multiple myeloma: novel agents, antibodies, immunotherapies and beyond". Leukemia. 32 (2): 252–262. doi:10.1038/leu.2017.329. PMC 5808071. PMID 29257139.CS1 maint: multiple names: authors list (link)
  6. ^ Barrett, Jennifer (2019-07-03). "New Treatment for Refractory Multiple Myeloma Granted FDA Approval". Pharmacy Times. Retrieved 2019-07-07.
  7. ^ a b c d e f g "XPOVIO Prescribing Information" (PDF). Newton, MA: Karyopharm Therapeutics. 2019-07-03. Retrieved 2019-07-06.
  8. ^ a b Chen C, Siegel D, Gutierrez M, Jacoby M, Hofmeister CC, Gabrail N (2018). "Safety and efficacy of selinexor in relapsed or refractory multiple myeloma and Waldenstrom macroglobulinemia". Blood. 131 (8): 855–863. doi:10.1182/blood-2017-08-797886. PMID 29203585.CS1 maint: multiple names: authors list (link)
  9. ^ a b c d Parikh K, Cang S, Sekhri A, Liu D; et al. (2014). "Selective inhibitors of nuclear export (SINE)—a novel class of anti-cancer agents". J Hematol Oncol. 7: 78. doi:10.1186/s13045-014-0078-0. PMC 4200201. PMID 25316614.CS1 maint: multiple names: authors list (link)