URMC-099 facilitates amyloid-β clearance in a murine model of Alzheimer’s disease

Kiyota, Tomomi; Machhi, Jatin; Lu, Yaman; Dyavarshetty, Bhagyalaxmi; Nemati, Maryam; Zhang, Gang; Mosley, R. Lee; Gelbard, Harris A.; Gendelman, Howard E.

doi:10.1186/s12974-018-1172-y

Cited by 34 publications

(52 citation statements)

References 75 publications

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“…MMV1581558, MMV021759, URMC-099-C, MMV1634394, nitazoxanide, clemizole, and selinexor all demonstrated IC 50 s ≤ 10 µM against B. mandrillaris. The mixed lineage kinase type 3 inhibitor, URMC-099-C, is known to induce amyloid-beta clearance in mouse Alzheimer's models [51,52]. Though shown to be toxic, the brain-penetrating property of this molecule makes it an interesting lead compound for future drug discovery efforts.…”

Section: Discussionmentioning

confidence: 99%

Discovery of Anti-Amoebic Inhibitors from Screening the MMV Pandemic Response Box on Balamuthia mandrillaris, Naegleria fowleri, and Acanthamoeba castellanii

et al. 2020

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Pathogenic free-living amoebae, Balamuthia mandrillaris, Naegleria fowleri, and several Acanthamoeba species are the etiological agents of severe brain diseases, with case mortality rates > 90%. A number of constraints including misdiagnosis and partially effective treatments lead to these high fatality rates. The unmet medical need is for rapidly acting, highly potent new drugs to reduce these alarming mortality rates. Herein, we report the discovery of new drugs as potential anti-amoebic agents. We used the CellTiter-Glo 2.0 high-throughput screening methods to screen the Medicines for Malaria Ventures (MMV) Pandemic Response Box in a search for new active chemical scaffolds. Initially, we screened the library as a single-point assay at 10 and 1 µM. From these data, we reconfirmed hits by conducting quantitative dose–response assays and identified 12 hits against B. mandrillaris, 29 against N. fowleri, and 14 against A. castellanii ranging from nanomolar to low micromolar potency. We further describe 11 novel molecules with activity against B. mandrillaris, 22 against N. fowleri, and 9 against A. castellanii. These structures serve as a starting point for medicinal chemistry studies and demonstrate the utility of phenotypic screening for drug discovery to treat diseases caused by free-living amoebae.

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Section: Discussionmentioning

confidence: 99%

Discovery of Anti-Amoebic Inhibitors from Screening the MMV Pandemic Response Box on Balamuthia mandrillaris, Naegleria fowleri, and Acanthamoeba castellanii

et al. 2020

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“…72 The utility of this agent is further strengthened by its ability to reverse neuroinflammatory and synaptic damage in the APP/PS-1 model of AD. 73…”

Section: F I G U R Ementioning

confidence: 99%

Neurovascular and immune mechanisms that regulate postoperative delirium superimposed on dementia

Wang

Velagapudi

Kong

et al. 2020

Alzheimer's & Dementia

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Objective: The present work evaluates the relationship between postoperative immune and neurovascular changes and the pathogenesis of surgery-induced delirium superimposed on dementia. Background and rationale: Postoperative delirium is a common complication in many older adults and in patients with dementia including Alzheimer's disease (AD). The course of delirium can be particularly debilitating, while its pathophysiology remains poorly defined. Historical evolution: As of 2019, an estimated 5.8 million people of all ages have been diagnosed with AD, 97% of whom are >65 years of age. Each year, many of these patients require surgery. However, anesthesia and surgery can increase the risk for further cognitive decline. Surgery triggers neuroinflammation both in animal models and in humans, and a failure to resolve this inflammatory state may contribute to perioperative neurocognitive disorders as well as neurodegenerative pathology. Updated hypothesis: We propose an immunovascular hypothesis whereby dysregulated innate immunity negatively affects the blood-brain interface, which triggers delirium and thereby exacerbates AD neuropathology. Early experimental data: We have developed a translational model to study delirium superimposed on dementia in APPSwDI/mNos2 −/− AD mice (CVN-AD) after orthopedic surgery. At 12 months of age, CVN-AD showed distinct neuroimmune and vascular impairments after surgery, including acute microgliosis and amyloid-deposition. These changes correlated with attention deficits, a core feature of delirium-like behavior. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. c

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“…URMC-099 is a brain-penetrant small molecule designed to inhibit MLK3 that has attenuated proinflammatory microglial activation and protected against neuronal and synaptic damage in models of neuroinflammatory disease in vitro and in vivo (Marker et al, 2013; Dong et al, 2016; Kiyota et al, 2018). Here, we investigated whether URMC-099 treatment could protect synapses and hippocampal function in mice with EAE.…”

Section: Introductionmentioning

confidence: 99%

The Mixed-Lineage Kinase Inhibitor URMC-099 Protects Hippocampal Synapses in Experimental Autoimmune Encephalomyelitis

Bellizzi

Hammond

et al. 2018

eNeuro

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Treatments to stop gray matter degeneration are needed to prevent progressive disability in multiple sclerosis (MS). We tested whether inhibiting mixed-lineage kinases (MLKs), which can drive inflammatory microglial activation and neuronal degeneration, could protect hippocampal synapses in C57BL/6 mice with experimental autoimmune encephalomyelitis (EAE), a disease model that recapitulates the excitatory synaptic injury that occurs widely within the gray matter in MS. URMC-099, a broad spectrum MLK inhibitor with additional activity against leucine-rich repeat kinase 2 (LRRK2) and other kinases, prevented loss of PSD95-positive postsynaptic structures, shifted activated microglia toward a less inflammatory phenotype, and reversed deficits in hippocampal-dependent contextual fear conditioning in EAE mice when administered after the onset of motor symptoms. A narrow spectrum inhibitor designed to be highly selective for MLK3 failed to protect synapses in EAE hippocampi, and could not rescue cultured neurons from trophic deprivation in an in vitro model of MLK-driven neuronal degeneration. These results suggest that URMC-099 may have potential as a neuroprotective treatment in MS and demonstrate that a broad spectrum of inhibition against a combination of MLK and other kinases is more effective in neuroinflammatory disease than selectively targeting a single kinase.

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URMC-099 facilitates amyloid-β clearance in a murine model of Alzheimer’s disease

Cited by 34 publications

References 75 publications

Discovery of Anti-Amoebic Inhibitors from Screening the MMV Pandemic Response Box on Balamuthia mandrillaris, Naegleria fowleri, and Acanthamoeba castellanii

Discovery of Anti-Amoebic Inhibitors from Screening the MMV Pandemic Response Box on Balamuthia mandrillaris, Naegleria fowleri, and Acanthamoeba castellanii

Neurovascular and immune mechanisms that regulate postoperative delirium superimposed on dementia

The Mixed-Lineage Kinase Inhibitor URMC-099 Protects Hippocampal Synapses in Experimental Autoimmune Encephalomyelitis

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