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

Marker, Daniel F.; Tremblay, Marie‐Ève; Puccini, Jenna M.; Barbieri, Justin; Marker, Mary A. Gantz; Loweth, Colin J.; Muly, E Christopher; Lu, Shao‐Ming; Goodfellow, Val S.; Dewhurst, Stephen; Gelbard, Harris A.

doi:10.1523/jneurosci.0598-13.2013

Cited by 66 publications

(106 citation statements)

References 54 publications

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“…URMC099 appears to be well tolerated in mice without noted adverse effects, consistent with our previous data with longer duration of URMC099 treatment in a different disease model (25,40). Here, we demonstrate that macrophage-associated inflammation is a key player in the MLK3-mediated sterile inflammatory response observed 30-minute 10 μM LPC treatment, nuclear localization of p65 in BMDMs was assessed by immunocytochemistry and confocal microscopy.…”

Section: Discussionsupporting

confidence: 90%

“…URMC099 is a selective small-molecule MLK3 pharmacological inhibitor that was developed for human use. URMC099 has nanomolar potency for MLK3 inhibition and a favorable metabolic and toxicity profile (25). Herein, we demonstrate a reduction in liver inflammation, liver injury, and fibrosis in URMC099-treated mice, independent of effects on weight gain and parameters of the metabolic syndrome.…”

Section: Introductionmentioning

confidence: 64%

“…Furthermore, mice fed the NASH-inducing diet have increased CXCL10 in plasma EVs in an MLK3-dependent fashion (23), and CXCL10 -/-mice are protected against diet-induced NASH (24). Likewise, MLK3 proinflammatory properties have been recently recognized in different disease models (25)(26)(27).…”

Section: Introductionmentioning

confidence: 99%

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Mixed-lineage kinase 3 pharmacological inhibition attenuates murine nonalcoholic steatohepatitis

Tomita¹,

Kohli²,

MacLaurin³

et al. 2017

JCI Insight

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 64%

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Mixed-lineage kinase 3 pharmacological inhibition attenuates murine nonalcoholic steatohepatitis

Tomita¹,

Kohli²,

MacLaurin³

et al. 2017

JCI Insight

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“…On the basis of the presumptive interactions between endosomal trafficking, cytoskeletal rearrangement, and Rab proteins, we began to explore known pathways that affect cellular trafficking to elucidate the underlying mechanism. Prior associations of URMC-099 with the phosphorylation of p54 and p46 JNK isoforms in HIV-Tat-treated BV-2 microglial cells provided mechanistic clues (48). However, while autophagy is a well-accepted cellular process involved in the recycling of cytoplasmic organelles, macromolecules, and other defective proteins (27), its role in establishing the types of drug depots and sequestration of drug-laden nanoparticles is far from proven.…”

Section: Discussionmentioning

confidence: 99%

“…We treated HIV-1 ADA strain-infected (HIV-1 ADA -infected) MDMs with 400 ng/ml URMC-099, followed by subtherapeutic concentrations (1 μM) of nanoformulated ATV (nanoATV) at 1, 3, and 5 days after infection at a multiplicity of 0.1 infectious virions per cell. The concentration of URMC-099 used elicited a maximal therapeutic efficacy that included drug particle retentions, amyloid β clearance, cellular vitality, and robust neuroprotective and antiinflammatory responses (11,(16)(17)(18)(19)(20). As concentrations of nanoATV of 100 μM or greater suppress viral replication, we performed URMC-099 dose-response determinations using subtherapeutic nanoATV concentrations for the measurement of viral growth.…”

Section: Urmc-099 Facilitates Nanoart Activitymentioning

confidence: 99%

Autophagy facilitates macrophage depots of sustained-release nanoformulated antiretroviral drugs

Gnanadhas¹,

Dash²,

Sillman³

et al. 2017

Journal of Clinical Investigation

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Long-acting anti-HIV products can substantively change the standard of care for patients with HIV/AIDS. To this end, hydrophobic antiretroviral drugs (ARVs) were recently developed for parenteral administration at monthly or longer intervals. While shorter-acting hydrophilic drugs can be made into nanocarrier-encased prodrugs, the nanocarrier encasement must be boosted to establish long-acting ARV depots. The mixed-lineage kinase 3 (MLK-3) inhibitor URMC-099 provides this function by affecting autophagy. Here, we have shown that URMC-099 facilitates ARV sequestration and its antiretroviral responses by promoting the nuclear translocation of the transcription factor EB (TFEB). In monocyte-derived macrophages, URMC-099 induction of autophagy led to retention of nanoparticles containing the antiretroviral protease inhibitor atazanavir. These nanoparticles were localized within macrophage autophagosomes, leading to a 4-fold enhancement of mitochondrial and cell vitality. In rodents, URMC-099 activation of autophagy led to 50-fold increases in the plasma drug concentration of the viral integrase inhibitor dolutegravir. These data paralleled URMC-099-mediated induction of autophagy and the previously reported antiretroviral responses in HIV-1-infected humanized mice. We conclude that pharmacologic induction of autophagy provides a means to extend the action of a long-acting, slow, effective release of antiretroviral therapy. Center for Neural Development and Disease, University of Rochester Medical Center (URMC), Rochester, New York, USA. Conflict of interest:H.A. Gelbard and H.E. Gendelman are members of the scientific advisory board for WavoDyne Therapeutics Inc., which is developing URMC-099 as a firstin-class MLK-3 inhibitor for clinical trials. URMC-099 is owned by URMC (patent nos. US 8,846,909 B2;8,877,772;and 9,181,247 and associated international patents). tion of TFEB mRNA by approximately 4-to 8-fold under different treatment conditions ( Figure 2F). With HIV-1 infection, TFEB mRNA levels were reduced by 2-to 3-fold compared with levels in uninfected controls, and URMC-099 could recover the phenotype. Increased TFEB translocation was delayed and did not reach significant levels until day 7 after URMC-099 treatment (Supplemental Figure 2B). These data confirm that URMC-099 regulates TFEB nuclear translocation in an mTORC1-dependent manner. URMC-099 stimulates autophagy in human MDMs. On the basis of the preceding data sets, we theorized that nuclear translocation of TFEB induces autophagy and lysosomal biogenesis. TFEB serves as the master regulator of both autophagy and lysosomal biogenesis (26), and such regulation could have a profound role in nanoART intracellular sequestration in MDMs. Thus, we examined the autophagosome markers microtubule-associated protein 1 light chain 3 β (LC3B, also known as MAP1LC3B) and beclin 1 (BECN1). Using Western blot assays, we found that each marker was significantly upregulated by URMC-099 ( Figure 3, A-C and Supplemental Figure 3A). URMC-099 increased the expression ...

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Dark microglia: A new phenotype predominantly associated with pathological states

Bisht¹,

Sharma²,

Lecours³

et al. 2016

Glia

341

435

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The past decade has witnessed a revolution in our understanding of microglia. These immune cells were shown to actively remodel neuronal circuits, leading to propose new pathogenic mechanisms. To study microglial implication in the loss of synapses, the best pathological correlate of cognitive decline across chronic stress, aging, and diseases, we recently conducted ultrastructural analyses. Our work uncovered the existence of a new microglial phenotype that is rarely present under steady state conditions, in hippocampus, cerebral cortex, amygdala, and hypothalamus, but becomes abundant during chronic stress, aging, fractalkine signaling deficiency (CX3CR1 knockout mice), and Alzheimer's disease pathology (APP‐PS1 mice). Even though these cells display ultrastructural features of microglia, they are strikingly distinct from the other phenotypes described so far at the ultrastructural level. They exhibit several signs of oxidative stress, including a condensed, electron‐dense cytoplasm and nucleoplasm making them as “dark” as mitochondria, accompanied by a pronounced remodeling of their nuclear chromatin. Dark microglia appear to be much more active than the normal microglia, reaching for synaptic clefts, while extensively encircling axon terminals and dendritic spines with their highly ramified and thin processes. They stain for the myeloid cell markers IBA1 and GFP (in CX3CR1‐GFP mice), and strongly express CD11b and microglia‐specific 4D4 in their processes encircling synaptic elements, and TREM2 when they associate with amyloid plaques. Overall, these findings suggest that dark microglia, a new phenotype that we identified based on their unique properties, could play a significant role in the pathological remodeling of neuronal circuits, especially at synapses. GLIA 2016;64:826–839

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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

Cited by 66 publications

References 54 publications

Mixed-lineage kinase 3 pharmacological inhibition attenuates murine nonalcoholic steatohepatitis

Mixed-lineage kinase 3 pharmacological inhibition attenuates murine nonalcoholic steatohepatitis

Autophagy facilitates macrophage depots of sustained-release nanoformulated antiretroviral drugs

Dark microglia: A new phenotype predominantly associated with pathological states

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