verdinexor (KPT-335) / Karyopharm, Anivive, Antengene - LARVOL DELTA

Therapeutic horizons in targeting XPO1 with small inhibitor molecules: Recent achievements, synthetic strategies, opportunities, challenges, and future perspectives. (PubMed, Bioorg Chem) - "The FDA approval of Selinexor marked a major milestone followed by second-generation compounds such as Eltanexor and Verdinexor. This review highlights the therapeutic applications, biological roles, the mechanisms of inhibition, recent preclinical and clinical achievements, and emerging opportunities in anticancer and antiviral therapeutics mediated by XPO1 inhibition. Specifically, this review emphasizes the detailed adopted chemical strategies for the development of XPO1 small molecule inhibitors and their emerging inhibition mechanisms, aiming to support future XPO1 inhibitor design."

Journal • Review • Oncology

Combination effect of Exportin 1 inhibitor (KPT-335) with doxorubicin or vincristine in canine lymphoma cell lines. (PubMed, J Vet Med Sci) - "Combination treatments significantly suppressed cell proliferation compared with single agents. These findings highlight the preclinical evidence of combining KPT-335 with conventional chemotherapies in canine lymphoma."

IO biomarker • Journal • Preclinical • Hematological Malignancies • Lymphoma • Oncology • XPO1

Pharmacologic Inhibition of XPO1 By Selinexor Improves Late-Stage Erythropoiesis in Severely Affected β0-Thalassemia/Hemoglobin E (ASH 2023) - "Nine compounds with known XPO1 inhibitory effect including five synthetic (KPT-185, KPT-276, KPT-330 or selinexor, KPT-335 or verdinexor and KPT-8602 or eltanexor) and four natural active compounds (curcumin, oridonin, piperlongumine and plumbagin) were evaluated in patient-derived HSPCs (n=1) for their potency and efficacy. Therefore, repurposing of selinexor to improve ineffective erythropoiesis in β-thalassemia is compelling. Moreover, combination treatments of selinexor with HbF inducers and/or SMAD2/3 blockers could be further validated to possibly achieve greater therapeutic benefits for β-thalassemia treatments."

IO biomarker • Beta-Thalassemia • Genetic Disorders • Hematological Malignancies • Multiple Myeloma • Myelofibrosis • Oncology • CD34 • GATA1 • SMAD2 • TFRC

Inhibition of XPO1 by selinexor enhances terminal erythroid maturation through modulation of HSP70 trafficking in severe β0-thalassemia/HbE. (PubMed, PLoS One) - "In this study, we screened nine XPO1 inhibitors, including the natural compounds curcumin, piperlongumine, plumbagin, and oridonin, as well as the synthetic agents KPT-185, KPT-276, selinexor, verdinexor, and eltanexor, in erythroid progenitors from patients with severe β0-thalassemia/HbE to identify the most effective inducer of TEM and to investigate the downstream molecular mechanisms involved...Combination treatments with hydroxyurea (a γ-globin inducer) and SIS3 (a SMAD3 inhibitor) confirmed selinexor's dominant effect...These findings suggest that cytoplasmic HSP70 trafficking may contribute to erythroid maturation in severe β0-thalassemia/HbE, implicating regulatory pathways beyond nuclear GATA1 stabilization. Collectively, our findings highlight the therapeutic potential of repurposing selinexor to enhance erythroid maturation in β-thalassemia and suggest that cytoplasmic HSP70 trafficking warrants further investigation as a contributor to terminal erythroid..."

Journal • Beta-Thalassemia • Genetic Disorders • Hematological Disorders • GATA1 • SMAD3 • XPO1

Refractory Multiple Myeloma in a West Highland White Terrier: Clinical Presentations and Therapeutic Interventions. (PubMed, Animals (Basel)) - "This report presents the case of a seven-year-old West Highland White Terrier diagnosed with relapsed and refractory multiple myeloma (MM), managed using multiple treatment approaches, including conventional chemotherapy (melphalan, vincristine, doxorubicin, and dexamethasone), radiation therapy (RT), and novel agents such as the selective inhibitor of nuclear export (verdinexor), proteasome inhibitors (bortezomib, carfilzomib, and ixazomib), and tyrosine kinase inhibitors (TKIs; toceranib and sorafenib). Timely intervention, individualized dosing, and supportive care are essential for optimizing treatment outcomes. Further research is required to define effective combinations and integrate advanced care options, including stem cell transplantation and targeted antibody therapies, in veterinary MM."

Journal • Hematological Disorders • Hematological Malignancies • Multiple Myeloma • Oncology • Transplantation

Exportin 1 (XPO1) Expression and Effectiveness of XPO1 Inhibitor Against Canine Lymphoma Cell Lines. (PubMed, Vet Sci) - "The expression levels of XPO1 mRNA and protein were related; however, no correlation was found between those expression levels and the efficacy of KPT-335. These findings suggest that XPO1 may represent a promising target for therapeutic intervention in canine lymphoma."

IO biomarker • Journal • Preclinical • Hematological Malignancies • Immunology • Lymphoma • Oncology • XPO1

Pharmacokinetic evaluation and bioavailability of KPT-335 (Verdinexor) in cats. (PubMed, Front Vet Sci) - "This finding provides data support for guiding clinical dosing regimens. At the same dose, the absolute bioavailability of the tablet group was higher than that of the capsule group."

Journal • PK/PD data • Oncology

Interferon activation in bone marrow long-lived plasma cells in systemic lupus erythematosus. (PubMed, Front Immunol) - "While BM PC bind type I IFN receptor-blocking antibody anifrolumab, it is to a lesser degree than circulating B cells. Both SLE and HD BM-derived PC have increased survival compared to their PBL counterparts when treated with verdinexor. In summary, these findings show evidence of IFN activation in BM PC from SLE."

IO biomarker • Journal • Immunology • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus • SDC1 • STAT1

Clinical Remission of Cutaneous Lymphoma in a Dog Treated with Verdinexor. (PubMed, J Am Anim Hosp Assoc) - "The dog has continued twice-weekly treatments without any interruption and remains in complete remission 17 mo following initiation of verdinexor therapy. This case provides evidence for the utility of verdinexor in the treatment of canine cutaneous epitheliotropic T-cell lymphoma."

Journal • Hematological Malignancies • Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma

Development of a UPLC-MS/MS method for quantifying KPT-335 (Verdinexor) in feline plasma for a study of PK. (PubMed, Front Vet Sci) - "The AUC0-∞ was 1589.82 ± 1003.75 ng·mL-1·h. The purpose of this study was to develop a rapid and simple UPLC-MS/MS method to detect KPT-335 concentration in cat plasma and to conduct preliminary pharmacokinetic studies to support the future application of KPT-335 in felines."

Journal • Infectious Disease • Influenza • Oncology • Respiratory Diseases • XPO1

Efficacy of verdinexor for the treatment of naïve canine epitheliotropic cutaneous T-cell lymphoma: An open-label pilot study. (PubMed, Vet Dermatol) - "Verdinexor could be considered a safe, palliative treatment for canine CETL."

Journal • Cutaneous T-cell Lymphoma • Dermatology • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Palliative care • Pruritus • Solid Tumor • T Cell Non-Hodgkin Lymphoma

Rapid and high-purity differentiation of human medium spiny neurons reveals LMNB1 hypofunction and subtype necessity in modeling Huntington's disease. (PubMed, Inflamm Regen) - "This study thus establishes an effective method for obtaining MSNs and underscores the necessity of using high-purity MSNs to study HD pathogenesis, especially the MSN-selective vulnerability."

Journal • CNS Disorders • Huntington's Disease • Movement Disorders • LMNB1

Medicines for Malaria Venture Pandemic Box In Vitro Screening Identifies Compounds Highly Active against the Tachyzoite Stage of Toxoplasma gondii. (PubMed, Trop Med Infect Dis) - "Treatment with 0.25 µM verdinexor, 3 nM MMV1580844, and 0.25 µM MMV019724 induced extensive vacuolization, complete ultrastructural disorganization, and lytic effects in the parasite, respectively, and all of them showed alterations in the division process. Treatment with 1 µM Eberconazole, 0.5 µM MMV1593541, 1 µM MMV642550, 1 µM RWJ-67657, and 1 µM URMC-099-C also caused extensive vacuolization in the parasite. The activity of these drugs against intracellular tachyzoites supports the idea that the drugs selected in the Pandemic Box could be potential future drugs for the treatment of acute toxoplasmosis."

Journal • Preclinical • Human Immunodeficiency Virus • Infectious Disease • Malaria

Assessment of verdinexor as a canine P-glycoprotein substrate. (PubMed, J Vet Pharmacol Ther) - "This study used a cell line overexpressing canine P-gp to assess the P-gp substrate status of verdinexor. Based on both a cytotoxicity assay and a competitive flow cytometry assay verdinexor is not a substrate for canine P-gp."

Journal • Oncology • ABCB1

EXPRESSION OF UNSPLICED HIV-1 RNA INDUCES INFLAMMASOME ACTIVATION IN MYELOID CELLS (CROI 2023) - "IL-1β production was independent of viral icRNA sequence, viral protein (Gag-Pol, Vif, Vpr, Vpu, Nef and Env) expression, and was attenuated upon pre-treatment with HIV-1 RT (Efavirenz), integrase (Raltegravir), transcription (Spironolactone) or icRNA export (KPT335) inhibitors, or treatment with a pan-caspase inhibitor (z-VAD). These results suggest that provirus establishment and persistent cytoplasmic expression of HIV-1 icRNA alone, even in the absence of viral protein expression, is sufficient to activate inflammasomes and might contribute to chronic innate immune activation."

Human Immunodeficiency Virus • Immunology • Infectious Disease • Inflammation • IL18 • IL1B • NLRP3 • STING

Characterization of the Interaction Between SARS-CoV-2 Membrane Protein (M) and Proliferating Cell Nuclear Antigen (PCNA) as a Potential Therapeutic Target. (PubMed, Front Cell Infect Microbiol) - "In addition, the inhibition of PCNA translocation by PCNA I1 and Verdinexor led to a reduction of plaque formation in an in vitro assay. We, therefore, propose that the transport of PCNA to the cytoplasm and its association with M could be a virus strategy to manipulate cell functions and may be considered a target for COVID-19 therapy."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases • PCNA

Verdinexor, a Selective Inhibitor of Nuclear Exportin 1, Inhibits the Proliferation and Migration of Esophageal Cancer via XPO1/c-Myc/FOSL1 Axis. (PubMed, Int J Biol Sci) - "Taken together, verdinexor inhibited cell proliferation and migration of esophageal cancer via XPO1/c-Myc/FOSL1 axis. Our findings provide a new option for the development of anti-esophageal cancer drugs."

IO biomarker • Journal • Esophageal Cancer • Gastrointestinal Cancer • Oncology • MYC • XPO1

COVID-19, Influenza and RSV: Surveillance-informed prevention and treatment - Meeting report from an isirv-WHO virtual conference. (PubMed, Antiviral Res) - "Potential therapeutics for SARS-CoV-2 included host-targeted therapies baricitinib, a JAK inhibitor, tocilizumab, an IL-6R inhibitor, verdinexor and direct acting antivirals ensovibep, S-217622, AT-527, and monoclonal antibodies casirivimab and imdevimab, directed against the spike protein. Data from trials of nirsevimab, a monoclonal antibody with a prolonged half-life which binds to the RSV F-protein, and an Ad26.RSV pre-F vaccine were also presented. The expanded role of the WHO Global Influenza Surveillance and Response System to address the SARS-CoV-2 pandemic was also discussed. This report summarizes the oral presentations given at this meeting for the benefit of the broader medical and scientific community involved in surveillance, treatment and prevention of respiratory virus diseases."

Journal • Review • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases • Respiratory Syncytial Virus Infections

Reversible disruption of XPO1-mediated nuclear export inhibits respiratory syncytial virus (RSV) replication. (PubMed, Sci Rep) - "In this study, we have investigated the anti-RSV efficacy of Selective Inhibitor of Nuclear Export (SINE) compounds, KPT-335 and KPT-185...Notably, the effect of SINE compounds was reversible within 24 h after their removal. Our data show that reversible inhibition of XPO1 can disrupt RSV replication by affecting downstream pathways regulated by the nuclear exporter."

IO biomarker • Journal • Infectious Disease • Respiratory Diseases • Respiratory Syncytial Virus Infections • XPO1

XPO1/CRM1 is a promising prognostic indicator for neuroblastoma and represented a therapeutic target by selective inhibitor verdinexor. (PubMed, J Exp Clin Cancer Res) - "XPO1 is a promising prognostic indicator for neuroblastoma and a novel target for antitumor treatment with selective inhibitor verdinexor."

Biomarker • IO biomarker • Journal • Neuroblastoma • Oncology • Solid Tumor • FOXO1 • RB1 • XPO1

"Verdinexor (similar properties to Selinexor) is being studied for canine lymphoma. Hopefully they succeed. https://t.co/QZxXeaa0sz" (@Biotech2050)

Hematological Malignancies • Lymphoma • Oncology

"Dr Leonard have a look at the embedded link to verdinexor @Pharmdca @semodough" (@Biotech2050)

The selective inhibitor of nuclear export (SINE) verdinexor exhibits biologic activity against canine osteosarcoma cell lines. (PubMed, Vet Comp Oncol) - "In the present study, we sought to characterize the expression of XPO1 in primary canine osteosarcoma (OS) tumor samples, OS cell lines and normal osteoblasts and evaluate the in vitro activity of verdinexor alone or in combination with doxorubicin. Concordantly, OS cell lines showed increased ?H2A.X foci following treatment with doxorubicin and recovery in verdinexor compared to cells treated with doxorubicin and recovered in normal media for 24?hours. These findings demonstrate that verdinexor has biologic activity against canine OS cell lines at physiologically relevant doses and suggest that XPO1 inhibition in combination with standard doxorubicin treatment offers promising potential for chemotherapeutic intervention in canine OS."

IO biomarker • Journal • Preclinical • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • CASP3

Effects of cadmium on osteoblast cell line: Exportin 1 accumulation, p-JNK activation, DNA damage and cell apoptosis. (PubMed, Ecotoxicol Environ Saf) - "Cd-induced cell survival enhanced by SP600125 but rescued by Z-VAD-FMK or KPT-335. These results suggest that cadmium cytotoxicity on bone involved exportin 1 accumulation, phosphorylation of JNK, induction of DNA damage and pro-apoptosis, which was induced by activation of caspase-dependent pathways."

Journal • Preclinical • Orthopedics • CASP3 • CASP9 • MAPK8 • STC2

[VIRTUAL] Impact of Selective Inhibitors of Nuclear Export on SLE Plasma Cells Is Modulated by the BM Microenvironment (ACR-ARHP 2020) - "Selective inhibitors of nuclear export (SINE) were recently approved by the FDA for treatment of refractory multiple myeloma (selinexor)... Peripheral blood mononuclear cells (PBMCs) and bone marrow mononuclear cells (BMMCs) from healthy (n = 4) and SLE donors (n = 4), cultured in the presence of mesenchymal stromal cell secretome, were treated with KPT-335 for different periods of time... SINEs represent a novel treatment approach for SLE. These results support the hypothesis that the effect of SINEs on PC depends upon the dose and duration of treatment, and is modulated by BM microenvironmental signals that orchestrate PC survival."

Complement-mediated Rare Disorders • Glomerulonephritis • Hematological Malignancies • Immunology • Inflammatory Arthritis • Lupus • Lupus Nephritis • Multiple Myeloma • Nephrology • Oncology • Systemic Lupus Erythematosus • CD19