URMC-099

URMC-099 is an orally bioavailable and brain penetrant inhibitor of MLK3 with IC50 value of 14 nM [1].

Mixed Lineage Kinase 3 (MLK3) is a member of the serine/threonine kinase family that regulate MAPK8/JNK signaling cascade and also activates ERK and p38. MLK3 activation can result in the stimulation of cell motility and migration [1] [2].

URMC-099 is a novel and orally bioavailable MLK3 inhibitor. In murine BV-2 microglial cells, URMC-099 inhibited LPS-induced TNFαrelease. In primary human monocytes, URMC-099 inhibited HIV-1 Tat-induced release of cytokines [1]. In neutrophils, URMC-099 reduced chemotaxis induced by fMLP and inhibited fMLP-stimulated F-actin formation [2].

In Tat-injected brains of mice, URMC-099 inhibited up-regulation of phospho-JNK. In HIV-1 Associated Neurocognitive Disorders (HAND) preclinical models, URMC-099 inhibited multiple kinase pathways, including MLK3 and LRRK2 (IC50 = 11 nM). URMC-099 reduced inflammatory cytokine production, protected neuronal architecture, and altered the morphologic and ultrastructural response of microglia to HIV-1 Tat exposure [1] [3]. In wild-type C57Bl/6 mice, URMC-099 inhibited fMLP-induced accumulation of neutrophils in the peritoneum [2]. In infected humanized NOD/SCID/IL2Rγc-/-mice, URMC-099 administered with nanoATV dose-dependently reduced HIV-1p24 viral load and reverse transcriptase activity, as well as the numbers of HIV-1 infected CD4+ T-cells in lymphoid tissues [4].

References:
[1].  Goodfellow VS, Loweth CJ, Ravula SB, et al. Discovery, synthesis, and characterization of an orally bioavailable, brain penetrant inhibitor of mixed lineage kinase 3. J Med Chem, 2013, 56(20): 8032-8048.
[2].  Polesskaya O, Wong C, Lebron L, et al. MLK3 regulates fMLP-stimulated neutrophil motility. Mol Immunol, 2014, 58(2): 214-222.
[3].  Marker DF, Tremblay MÈ, Puccini JM, et al. 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. J Neurosci, 2013, 33(24): 9998-10010.
[4].  Zhang G, Guo D, Dash PK, et al. The Mixed Lineage Kinase-3 Inhibitor URMC-099 Improves Therapeutic Outcomes for Long-Acting Antiretroviral Therapy. Nanomedicine, 2015. pii: S1549-9634(15)00187-2.

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.[Pubmed:23761895]

J Neurosci. 2013 Jun 12;33(24):9998-10010.

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.

The mixed-lineage kinase 3 inhibitor URMC-099 facilitates microglial amyloid-beta degradation.[Pubmed:27401058]

J Neuroinflammation. 2016 Jul 11;13(1):184.

BACKGROUND: Amyloid-beta (Abeta)-stimulated microglial inflammatory responses engage mitogen-activated protein kinase (MAPK) pathways in Alzheimer's disease (AD). Mixed-lineage kinases (MLKs) regulate upstream MAPK signaling that include p38 MAPK and c-Jun amino-terminal kinase (JNK). However, whether MLK-MAPK pathways affect Abeta-mediated neuroinflammation is unknown. To this end, we investigated if URMC-099, a brain-penetrant small-molecule MLK type 3 inhibitor, can modulate Abeta trafficking and processing required for generating AD-associated microglial inflammatory responses. METHODS: Abeta1-42 (Abeta42) and/or URMC-099-treated murine microglia were investigated for phosphorylated mitogen-activated protein kinase kinase (MKK)3, MKK4 (p-MKK3, p-MKK4), p38 (p-p38), and JNK (p-JNK). These pathways were studied in tandem with the expression of the pro-inflammatory cytokines interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)-alpha. Gene expression of the anti-inflammatory cytokines, IL-4 and IL-13, was evaluated by real-time quantitative polymerase chain reaction. Abeta uptake and expression of scavenger receptors were measured. Protein trafficking was assessed by measures of endolysosomal markers using confocal microscopy. RESULTS: Abeta42-mediated microglial activation pathways were shown by phosphorylation of MKK3, MKK4, p38, and JNK and by expression of IL-1beta, IL-6, and TNF-alpha. URMC-099 modulated microglial inflammatory responses with induction of IL-4 and IL-13. Phagocytosis of Abeta42 was facilitated by URMC-099 with up-regulation of scavenger receptors. Co-localization of Abeta and endolysosomal markers associated with enhanced Abeta42 degradation was observed. CONCLUSIONS: URMC-099 reduced microglial inflammatory responses and facilitated phagolysosomal trafficking with associated Abeta degradation. These data demonstrate a new immunomodulatory role for URMC-099 to inhibit MLK and to induce microglial anti-inflammatory responses. Thus, URMC-099 may be developed further as a novel disease-modifying AD therapy.

The mixed lineage kinase-3 inhibitor URMC-099 improves therapeutic outcomes for long-acting antiretroviral therapy.[Pubmed:26472049]

Nanomedicine. 2016 Jan;12(1):109-22.

During studies to extend the half-life of crystalline nanoformulated antiretroviral therapy (nanoART) the mixed lineage kinase-3 inhibitor URMC-099, developed as an adjunctive neuroprotective agent was shown to facilitate antiviral responses. Long-acting ritonavir-boosted atazanavir (nanoATV/r) nanoformulations co-administered with URMC-099 reduced viral load and the numbers of HIV-1 infected CD4+ T-cells in lymphoid tissues more than either drug alone in infected humanized NOD/SCID/IL2Rgammac-/- mice. The drug effects were associated with sustained ART depots. Proteomics analyses demonstrated that the antiretroviral responses were linked to affected phagolysosomal storage pathways leading to sequestration of nanoATV/r in Rab-associated recycling and late endosomes; sites associated with viral maturation. URMC-099 administered with nanoATV induced a dose-dependent reduction in HIV-1p24 and reverse transcriptase activity. This drug combination offers a unique chemical marriage for cell-based viral clearance. From the Clinical Editor: Although successful in combating HIV-1 infection, the next improvement in antiretroviral therapy (nanoART) would be to devise long acting therapy, such as intra-cellular depots. In this report, the authors described the use of nanoformulated antiretroviral therapy given together with the mixed lineage kinase-3 inhibitor URMC-099, and showed that this combination not only prolonged drug half-life, but also had better efficacy. The findings are hoped to be translated into the clinical setting in the future.

URMC-099 is an orally bioavailable and potent mixed lineage kinase type 3 (MLK3) (IC50=14 nM) inhibitor with with excellent blood-brain barrier penetration properties.

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