Selinexor
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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. 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. 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. The FDA approved Selinexor in June 2019. 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.
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. 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. 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. The FDA approved Selinexor in June 2019. 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.
Selinexor binds to and inhibits exportin-1 (XPO1). 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. 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. 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. These wide ranging changes in protein expression and gene transcription culminate in cell cycle arrest and the promotion of apoptosis in cancer cells.
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. 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.
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