A5101668176- Nuclear Structure and Function
- Glioma Diagnosis and Treatment
- RNA Research and Splicing
- Parvovirus B19 Infection Studies
- Mitochondrial Function and Pathology
- Virus-based gene therapy research
- Cancer-related Molecular Pathways
- Radiopharmaceutical Chemistry and Applications
- Systemic Lupus Erythematosus Research
- Prostate Cancer Treatment and Research
- Respiratory viral infections research
- Muscle Physiology and Disorders
- Medical Imaging Techniques and Applications
- Cancer, Lipids, and Metabolism
- Viral Infections and Outbreaks Research
- Traumatic Brain Injury Research
- interferon and immune responses
- Amyotrophic Lateral Sclerosis Research
- RNA modifications and cancer
- Influenza Virus Research Studies
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Acute Myeloid Leukemia Research
- Traumatic Brain Injury and Neurovascular Disturbances
- HIV/AIDS drug development and treatment
- Autophagy in Disease and Therapy
Karyopharm Therapeutics (United States)
2014-2023
University of California, San Diego
2023
Cleveland Clinic Lerner College of Medicine
2022
Abstract Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are progressive neurodegenerative disorders marked in most cases by the nuclear exclusion cytoplasmic deposition of RNA binding protein TDP43. We previously demonstrated that ALS–associated mutant TDP43 accumulates within cytoplasm, mislocalization predicts neurodegeneration. Here, we sought to prevent neurodegeneration ALS/FTD models using selective inhibitor export (SINE) compounds target exportin-1 (XPO1). SINE...
Influenza is a global health concern, causing death, morbidity, and economic losses. Chemotherapeutics that target influenza virus are available; however, rapid emergence of drug-resistant strains common. Therapeutic targeting host proteins hijacked by to facilitate replication an antiviral strategy reduce the development drug resistance. Nuclear export ribonucleoprotein (vRNP) from infected cells has been shown be mediated exportin 1 (XPO1) interaction with viral nuclear protein tethered...
Abstract Purpose: Selinexor is an oral selective inhibitor of exportin-1 (XPO1) with efficacy in various solid and hematologic tumors. We assessed intratumoral penetration, safety, selinexor monotherapy for recurrent glioblastoma. Patients Methods: Seventy-six adults Karnofsky Performance Status ≥ 60 were enrolled. undergoing cytoreductive surgery received up to three doses (twice weekly) preoperatively (Arm A; n = 8 patients). not 50 mg/m2 B, 24), or mg C, 14) twice weekly, 80 once weekly...
The novel coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome 2 (SARS-CoV-2) is responsible for recent global pandemic. nuclear export protein (XPO1) has a direct role in of SARS-CoV proteins including ORF3b, ORF9b, and nucleocapsid. Inhibition XPO1 induces anti-inflammatory, anti-viral, antioxidant pathways. Selinexor an FDA-approved inhibitor. Through bioinformatics analysis, we predicted sequences ACE-2 confirmed vitro testing that inhibition with selinexor...
The capsid structural protein of the New World alphavirus, Venezuelan equine encephalitis virus (VEEV), interacts with host nuclear transport proteins importin α/β1 and CRM1. Novel selective inhibitor export (SINE) compounds, KPT-185, KPT-335 (verdinexor), KPT-350, target host's primary protein, CRM1, in a manner similar to archetypical Leptomycin B. One major limitation B is its irreversible binding CRM1; which SINE compounds alleviate because they are slowly reversible. Chemically...
RSV is an important cause of LRTI in infants and young children for which there are no suitable antiviral drugs offered. We evaluated the efficacy KPT-335 as anti-RSV drug show that inhibits XPO1-mediated nuclear export, leading to accumulation M protein reduction levels. treatment also resulted inhibition proinflammatory pathways, has implications its effectiveness vivo .
Infection of immunocompromised individuals with normally benign opportunistic viruses is a major health burden globally. Infections such as Epstein-Barr virus (EBV), human cytomegalovirus (HCMV), Kaposi's sarcoma (KSHV), adenoviruses (AdV), BK (BKPyV), John Cunningham (JCPyV), and papillomavirus (HPV) are significant concerns for the immunocompromised, including when these exist co-infection immunodeficiency (HIV). These viral infections more complicated in patients weakened immune system,...
Influenza A virus (IAV) causes seasonal epidemics of respiratory illness that can cause mild to severe and potentially death. Antiviral drugs are an important countermeasure against IAV; however, drug resistance has developed, thus new therapeutic approaches being sought. Previously, we demonstrated the antiviral activity a novel nuclear export inhibitor drug, verdinexor, reduce influenza replication in vitro pulmonary burden mice. In this study, vivo efficacy verdinexor was further...
Summary Background Exportin 1 ( XPO 1/ CRM 1) plays prominent roles in the regulation of nuclear protein export. Selective inhibitors export SINE ) are small orally bioavailable molecules that serve as drug‐like 1, with potent anti‐cancer properties. Traumatic brain injury TBI presents a secondary cell death characterized by neuroinflammation is putatively regulated receptors. Aims and Results Here, we report compounds KPT ‐350 or ‐335) sequestered ‐induced neuroinflammation‐related proteins...
Infection with HIV ultimately leads to advanced immunodeficiency resulting in an increased incidence of cancer. For example primary effusion lymphoma (PEL) is aggressive non-Hodgkin very poor prognosis that typically affects infected individuals stages immunodeficiency. Here we report on the dual anti-HIV and anti-PEL effect targeting a single process common both diseases. Inhibition exportin-1 (XPO1) mediated nuclear transport by clinical stage orally bioavailable small molecule inhibitors...
Duchenne muscular dystrophy (DMD) is an X-linked muscle wasting disease that caused by the loss of functional dystrophin protein in cardiac and skeletal muscles. DMD patient muscles become weakened, leading to eventual myofiber breakdown replacement with fibrotic adipose tissues. Inflammation drives pathogenic processes through releasing inflammatory cytokines other factors promote degeneration contributing motor function. Selective inhibitors nuclear export (SINEs) are a class compounds...
Abstract Respiratory syncytial virus (RSV) is the primary cause of serious lower respiratory tract disease in infants, young children, elderly and immunocompromised individuals. Therapy for RSV infections limited to high risk infants there are no safe efficacious vaccines. Matrix (M) protein a major structural with key role assembly. Interestingly, M localised nucleus early infection its export into cytoplasm by nuclear exporter, exportin-1 (XPO1) essential We have shown previously that...
Abstract Infection of immunocompromised individuals with normally benign opportunistic viruses is a major health burden globally. Infections such as Epstein-Barr virus (EBV), human cytomegalovirus (HCMV), Kaposi’s sarcoma (KSHV), adenoviruses (AdV), BK (BKPyV), John Cunningham (JCPyV), and papillomavirus (HPV) are significant concerns for the immunocompromised, including when these exist co-infection immunodeficiency (HIV). These viral infections more complicated in patients weakened immune...
We tested whether KPT-350, a novel selective inhibitor of nuclear export, could attenuate cortical network hyperexcitability, major risk factor for developing post-traumatic epilepsy (PTE) following traumatic brain injury (TBI).All mice in this study underwent TBI and were subsequently treated with either KPT-350 or vehicle during the post-injury latent period. Half animal cohort was used electrophysiology while other half immunohistochemical analysis.TBI induced using controlled impact...
Abstract Chromosomal Region Maintenance Protein 1/Exportin 1 (CRM1/XPO1) is a key nuclear export protein whose inhibition leads to the accumulation of Tumor Suppressor Proteins (TSPs) and renders cancer cells susceptible apoptosis. Selinexor orally bioavailable represents novel class small molecule compounds with potent activity against wide variety cancers. currently in Phase clinical studies hematological solid patients (Clinicaltrials.gov NCT01607892 NCT01607905). We tested soft tissue...
Duchenne muscular dystrophy (DMD) is a progressive, X-linked childhood neuromuscular disorder that results from loss-of-function mutations in the DYSTROPHIN gene. DMD patients exhibit muscle necrosis, cardiomyopathy, respiratory failure, and loss of ambulation. One major driving forces disease pathology chronic inflammation. The current standard care corticosteroids; however, there are serious side effects with long-term use, thus identifying novel anti-inflammatory anti-fibrotic treatments...
Objective To investigate the hypothesis that selective inhibitors of nuclear export (SINE compounds), recently approved for treatment refractory plasma cell (PC) malignancy, may have potential in lupus. Methods Female NZB/NZW mice were treated with SINE compound KPT‐350 or vehicle control. Tissue specimens harvested and analyzed by flow cytometry, using standard markers. Nephritis was monitored determining proteinuria score histologic analysis kidney specimens. Serum anti–double‐stranded DNA...
7060 Background: Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by unregulated, clonal proliferation of hematopoietic stem cells in the bone marrow and commonly associated with gene mutations JAK2, CALR, or MPL. Front-line therapy may include JAK1/2 inhibitor ruxolitinib (RUX), resulting spleen volume reductions improvement MF-related symptoms. Despite therapeutic effect RUX, most patients (pts) eventually progress thus novel combinations are required to increase responses...
10587 Background: Sarcomas are heterogeneous diseases with multiple genetic abnormalities. XPO1 inhibition can restore the activity of tumor suppressor proteins (TSP) including p53, Rb, and p27; reduce cyclins Akt. Selinexor is an oral inhibitor that showed potent anti-sarcoma in preclinical ASPS, lipo- bone sarcomas, preliminary clinical a phase 1 study. Methods: Oral selinexor was given at 30 mg/m2 twice weekly capsule or tablet form based on ongoing Phase 1. Appetite stimulants...
Abstract Selinexor (KPT-330) is a novel small molecule inhibitor of nuclear export through covalent binding to Exportin 1 (XPO1/CRM1) leading forced retention major tumor suppressor proteins (TSPs) such as p53, FOXO, pRB and IκB, resulting in selective death cancer cells. Preclinical studies have shown that oral well tolerated, even with prolonged (4-8 month) administration. Human Phase clinical hematological solid patients are ongoing (Clinicaltrials.gov NCT01607892 NCT01607905). In this...