ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2013
The new small-molecule mixed-lineage kinase 3 inhibitor URMC-099 is neuroprotective and anti-inflammatory in models of human immunodeficiency virus-associated neurocognitive disorders.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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Who cites it
46 citing papers in PubMed, 64 citations in OpenAlex.
- MLK3 promotes atherosclerosis by regulating ferroptosis in macrophages.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2026Article
- HIV-1 Tat-driven Glutamate Dysregulation: Implications for Cognitive Impairment in HAND.Current HIV/AIDS reports · 2026Review
- Hybrid Amyloid Quantum Dot Nano-Bio Assemblies to Probe Neuroinflammatory Damage.ACS chemical neuroscience · 2024Article
- Infectious Diseases.Advances in neurobiology · 2024Review
- Quantum Dot Biomimetic for SARS-CoV-2 to Interrogate Blood-Brain Barrier Damage Relevant to NeuroCOVID Brain Inflammation.ACS applied nano materials · 2023Article
- Mechanism and Therapeutic Targets of c-Jun-N-Terminal Kinases Activation in Nonalcoholic Fatty Liver Disease.Biomedicines · 2022Review
- URMC-099 prophylaxis prevents hippocampal vascular vulnerability and synaptic damage in an orthopedic model of delirium superimposed on dementia.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2022Article
- Enhancer promoter interactome and Mendelian randomization identify network of druggable vascular genes in coronary artery disease.Human genomics · 2022Article
- Mixed Lineage Kinase 3 phosphorylates prolyl-isomerase PIN1 and potentiates GLI1 signaling in pancreatic cancer development.Cancer letters · 2021Article
- Cannabidiol Inhibits SARS-CoV-2 Replication and Promotes the Host Innate Immune Response.bioRxiv : the preprint server for biology · 2021Article
- The regulatory function of mixed lineage kinase 3 in tumor and host immunity.Pharmacology & therapeutics · 2021Review
- Identification of an Antiviral Compound from the Pandemic Response Box that Efficiently Inhibits SARS-CoV-2 Infection In Vitro.Microorganisms · 2020Article
- Rationalized inhibition of mixed lineage kinase 3 and CD70 enhances life span and antitumor efficacy of CD8Journal for immunotherapy of cancer · 2020Article
- Pyroptosis and ferroptosis induced by mixed lineage kinase 3 (MLK3) signaling in cardiomyocytes are essential for myocardial fibrosis in response to pressure overload.Cell death & disease · 2020Article
- Discovery of Anti-Amoebic Inhibitors from Screening the MMV Pandemic Response Box onPathogens (Basel, Switzerland) · 2020Article
- Mixed lineage kinase 3 inhibition induces T cell activation and cytotoxicity.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Development of MAP4 Kinase Inhibitors as Motor Neuron-Protecting Agents.Cell chemical biology · 2019Article
- Inhibitory Control Deficits Associated with Upregulation of CBJournal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology · 2019Article
- The broad spectrum mixed-lineage kinase 3 inhibitor URMC-099 prevents acute microgliosis and cognitive decline in a mouse model of perioperative neurocognitive disorders.Journal of neuroinflammation · 2019Article
- Age-Related Decrease in Tyrosine Hydroxylase Immunoreactivity in the Substantia Nigra and Region-Specific Changes in Microglia Morphology in HIV-1 Tg Rats.Neurotoxicity research · 2019Article
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Authors and funding
11 authors at 6 institutions in 3 countries.
Funding
Abstract
Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) is a significant source of disability in the HIV-infected population. Even with stringent adherence to anti-retroviral therapy, >50% of patients living with HIV-1 will develop HAND (Heaton et al., 2010). Because suppression of viral replication alone is not enough to stop HAND progression, there is a need for an adjunctive neuroprotective therapy in this population. To this end, we have developed a small-molecule brain-penetrant inhibitor with activity against mixed-lineage kinase 3 (MLK3), named URMC-099. MLK3 activation is associated with many of the pathologic hallmarks of HAND (Bodner et al., 2002, 2004; Sui et al., 2006) and therefore represents a prime target for adjunctive therapy based on small-molecule kinase inhibition. Here we demonstrate the anti-inflammatory and neuroprotective effects of URMC-099 in multiple murine and rodent models of HAND. In vitro, URMC-099 treatment reduced inflammatory cytokine production by HIV-1 Tat-exposed microglia and prevented destruction and phagocytosis of cultured neuronal axons by these cells. In vivo, URMC-099 treatment reduced inflammatory cytokine production, protected neuronal architecture, and altered the morphologic and ultrastructural response of microglia to HIV-1 Tat exposure. In conclusion, these data provide compelling in vitro and in vivo evidence to investigate the utility of URMC-099 in other models of HAND with the goal of advancement to an adjunctive therapeutic agent.
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