|Metabolism||Hepatic oxidation, glucuronidation, and conjugation, by CYP3A4, UGT and GST|
|Elimination half-life||6–8 h|
|Chemical and physical data|
|Molar mass||443.313 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. It is the first drug with this mechanism of action.
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.
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), for whom no other treatment options are available. It is the first drug to be approved for this indication.
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%). 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. More than half of all patients who received the drug developed infections, including fatal cases of sepsis. However, these data are from an open-label trial, and thus cannot be compared to placebo or directly attributed to treatment.
Mechanism of action
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. 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. In vitro, this effect appeared to spare normal (non-malignant) cells.
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. 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.
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.
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.
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. 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. Compassionate use in patients with acute myeloid leukemia has also been reported.
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. 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); nearly all had also undergone hematopoietic stem cell transplantation to no effect. The overall response rate was 25%, and no patients had a complete response. However, the response rate was higher in patients with high-risk myeloma (cytogenetic abnormalities associated with a worse prognosis). The median time to progression was 2.3 months overall and 5 months in patients who responded to the drug.
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