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URMC-099

MLK3 inhibitor, orally bioavailable and brain penetrant CAS# 1229582-33-5

URMC-099

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Chemical structure

URMC-099

3D structure

Chemical Properties of URMC-099

Cas No. 1229582-33-5 SDF Download SDF
PubChem ID 54764565 Appearance Powder
Formula C27H27N5 M.Wt 421.54
Type of Compound N/A Storage Desiccate at -20°C
Solubility DMSO : ≥ 33 mg/mL (78.28 mM)
H2O : < 0.1 mg/mL (insoluble)
*"≥" means soluble, but saturation unknown.
Chemical Name 3-(1H-indol-5-yl)-5-[4-[(4-methylpiperazin-1-yl)methyl]phenyl]-1H-pyrrolo[2,3-b]pyridine
SMILES CN1CCN(CC1)CC2=CC=C(C=C2)C3=CN=C4C(=C3)C(=CN4)C5=CC6=C(C=C5)NC=C6
Standard InChIKey QKKIWEILHCXECO-UHFFFAOYSA-N
Standard InChI InChI=1S/C27H27N5/c1-31-10-12-32(13-11-31)18-19-2-4-20(5-3-19)23-15-24-25(17-30-27(24)29-16-23)21-6-7-26-22(14-21)8-9-28-26/h2-9,14-17,28H,10-13,18H2,1H3,(H,29,30)
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of URMC-099

DescriptionURMC-099 is an orally bioavailable, brain penetrant inhibitor of Mixed Lineage Kinase 3(MLK3) with IC50 of 14 nM; inhibits LPS-induced TNFα release in microglial cells, HIV-1 Tat-induced release of cytokines in human monocytes, and up-regulation of phospho-JNK in Tat-injected brains of mice. IC50 value: 14 nM [1] Target: MLK3 inhibitor in vitro: URMC-099 shows excellent brain exposure in mouse PK models and minimal interference with key human CYP450 enzymes or hERG channels. inhibits LPS-induced TNFα release in microglial cells, HIV-1 Tat-induced release of cytokines in human monocytes and up-regulation of phospho-JNK in Tat-injected brains of mice. URMC-099 likely functions in HAND preclinical models by inhibiting multiple kinase pathways, including MLK3 and LRRK2 (IC50 = 11 nM) [1]. 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 [2]. 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 [2].

References:
[1]. Goodfellow VS, et al. Discovery, synthesis, and characterization of an orally bioavailable, brain penetrant inhibitor of mixed lineage kinase 3. J Med Chem. 2013 Oct 24;56(20):8032-48. [2]. Marker DF, 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 Jun 12;33(24):9998-10010.

Protocol

Cell experiment [1]:

Cell lines

Human monocytes

Preparation method

Limited solubility. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.

Reacting condition

37oC

Applications

URMC-099 potently and dose-dependently inhibits TNF-α, MCP-1,IL-6, and IL-8 that are crucial to the pathogenesis of HAND (HIV-1 Associated Neurocognitive Disorders). In contrast to the Tat-only treatment, URMC-099 reaches at the lowest drug concentration tested (100 nM) for TNFα and IL-6, and at 300 nM for MCP1.

Animal experiment [2]:

Animal models

Tat exposure mouse model

Dosage form

Injection

Application

URMC-099 treatment before and after Tat exposure partially preserves normal Map2 staining at the Tat injection site. As Tat exposure markedly decreases puncta density at the injection site, the puncta density is restored to control levels by URMC-099 treatment. Furthermore, URMC-099 alters the morphology and neuronal interactions of microglia exposed to HIV-1 Tat.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

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 Oct 24;56(20):8032-48.

2. Marker DF, Tremblay M, 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 Jun 12;33(24):9998-10010.

URMC-099 Dilution Calculator

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Preparing Stock Solutions of URMC-099

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.3723 mL 11.8613 mL 23.7225 mL 47.4451 mL 59.3064 mL
5 mM 0.4745 mL 2.3723 mL 4.7445 mL 9.489 mL 11.8613 mL
10 mM 0.2372 mL 1.1861 mL 2.3723 mL 4.7445 mL 5.9306 mL
50 mM 0.0474 mL 0.2372 mL 0.4745 mL 0.9489 mL 1.1861 mL
100 mM 0.0237 mL 0.1186 mL 0.2372 mL 0.4745 mL 0.5931 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on 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.

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References on URMC-099

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.

Description

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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