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| Targets |
URMC-099 targets mixed-lineage kinases (MLKs), including MLK1, MLK2, MLK3, and DLK. MLKs are a family of serine/threonine protein kinases that play a critical role in stress-activated signaling pathways, including the JNK and p38 MAPK pathways. These pathways are involved in neuronal death, inflammation, and synaptic dysfunction in neurodegenerative diseases. URMC-099 also inhibits LRRK2, a kinase associated with Parkinson's disease. By inhibiting MLKs and LRRK2, URMC-099 modulates neuroinflammatory and neurodegenerative pathways. Its IC50 values are 19 nM (MLK1), 42 nM (MLK2), 14 nM (MLK3), 150 nM (DLK), and 11 nM (LRRK2).
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| ln Vitro |
It was investigated how URMC-099 (URMC099) affected the in vitro proliferation of "brain-homing" MDA-MB-231 BR cells that expressed eGFP (eGFP8.4) and the cell line that gave rise to them. Both the vehicle and 200 nM URMC-099 were used to treat the cells. The growth rate of cells treated with URMC-099 was comparable to that of cells treated with vehicle. All cases had cell viability greater than 99% [2].
In vitro, URMC-099 is a potent inhibitor of MLK1, MLK2, MLK3, DLK, and LRRK2. The compound has been shown to inhibit MLK3 with an IC50 of 14 nM. It also inhibits LRRK2 activity with an IC50 of 11 nM. Its potency and selectivity have been characterized in kinase activity assays using purified recombinant kinases. The compound's ability to modulate JNK and p38 MAPK signaling has been confirmed in cell-based assays. |
| ln Vivo |
The terminal elimination half-life of URMC-099 is intermediate for C57 BL/6 mice (10 mg/kg, p.o. ), mg/kg, iv), and C57 BL/6 mice (10 mg/kg, iv) with t1/2=1.92 h, 2.14 h, and 2.72 h[1]. URMC-099 (URMC099) was examined for its impact on tumor formation in vivo by means of a well-established mice xenograft model of brain metastasis from breast cancer. Immunodeficient nu/nu mice were used in these studies, and after injecting eGFP8.4 cells into their left ventricle, the animals were given either vehicle or URMC-099 (10 mg/kg) every 12 hours for 20 days. Because it has been demonstrated to be sufficient to inhibit MLK3 in mice, has strong penetration of the blood-brain barrier, and efficiently suppresses the phosphorylation of Jun N-terminal kinase (JNK) in brain tissue, this dosage of URMC-099 was selected. Mice were slaughtered on day 21 and the BM number was determined. Each treatment group included of fifteen mice. 60% of the animals had BM, which is in line with other researchers' earlier investigations utilizing this xenograft model. The total number of brain metastases (BM) in mice was significantly (p<0.05, two-tailed t-test) increased by URMC-099 therapy. The pattern for micrometastases was comparable to the overall BM pattern. The number of macrometastases in mice treated with vehicle or URMC-099 was not significantly different [2].
In vivo, URMC-099 has been studied for the treatment of Parkinson's disease and HIV-1 associated neurocognitive disorders. Its oral bioavailability and brain penetration make it suitable for CNS applications. URMC-099 has demonstrated neuroprotective effects in preclinical models of neurodegeneration and neuroinflammation. Its inhibition of MLKs and LRRK2 suggests potential therapeutic applications in Parkinson's disease and other neurodegenerative disorders. |
| Enzyme Assay |
In vitro enzyme/receptor binding (non-cell) assays for URMC-099 involve measuring its inhibitory activity against MLK1, MLK2, MLK3, DLK, and LRRK2 using purified recombinant kinases. Kinase activity assays are performed with peptide substrates and ATP in the presence of varying concentrations of URMC-099. Kinase activity is measured by quantifying phosphorylation of the substrate, and IC50 values are calculated from inhibition curves.
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| Cell Assay |
In vitro cell-based experiments for URMC-099 are conducted using neuronal cell lines or primary neurons. Cells are treated with URMC-099 at varying concentrations, and cell viability, apoptosis, and neurite outgrowth are assessed. JNK and p38 MAPK phosphorylation is measured by Western blot to confirm target inhibition. The compound's neuroprotective effects against various stressors are evaluated.
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| Animal Protocol |
In vivo animal experiments for URMC-099 are performed in animal models of Parkinson's disease (e.g., MPTP or 6-OHDA models) and HIV-1 associated neurocognitive disorders. URMC-099 is administered orally, and behavioral tests, neuroinflammation markers, and neuronal survival are assessed. The compound's brain penetration and target engagement are confirmed by measuring drug levels and kinase inhibition in brain tissue.
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| ADME/Pharmacokinetics |
URMC-099 is orally bioavailable with good brain penetration. The compound has a molecular weight of 421.54 and a formula of C27H27N5. It is soluble in DMSO (≥25 mg/mL). Detailed pharmacokinetic parameters, including Cmax, Tmax, AUC, and half-life, are available from preclinical studies. Its favorable PK properties support its use in CNS research.
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| Toxicity/Toxicokinetics |
Preclinical toxicology studies have been conducted to evaluate the safety profile of URMC-099. The compound is well-tolerated at efficacious doses in animal models, with no significant off-target toxicity reported in available literature. Its selectivity for MLKs and LRRK2 suggests a favorable safety profile with minimal off-target effects. However, as with any kinase inhibitor, potential on-target effects on normal cellular functions should be considered.
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| References |
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| Additional Infomation |
Inhibit mixed lineage kinase 3
URMC-099 is a research compound used primarily for studying the role of mixed-lineage kinases and LRRK2 in neurodegenerative diseases and neuroinflammation. Its potent inhibition of MLK1, MLK2, MLK3, DLK, and LRRK2 makes it a valuable tool for exploring new therapeutic strategies for Parkinson's disease, HIV-1 associated neurocognitive disorders, and other CNS conditions. The compound is not approved for clinical use. |
| Molecular Formula |
C27H27N5
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| Molecular Weight |
421.5368
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| Exact Mass |
421.226
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| CAS # |
1229582-33-5
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| PubChem CID |
54764565
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| Appearance |
Off-white to yellow solid powder
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| Density |
1.3±0.1 g/cm3
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| Index of Refraction |
1.711
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| LogP |
3.85
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
32
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| Complexity |
611
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CN1CCN(CC1)CC2=CC=C(C=C2)C3=CC4=C(NC=C4C5=CC6=C(C=C5)NC=C6)N=C3
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| InChi Key |
QKKIWEILHCXECO-UHFFFAOYSA-N
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| InChi Code |
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)
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| Chemical Name |
3-(1H-indol-5-yl)-5-[4-[(4-methylpiperazin-1-yl)methyl]phenyl]-1H-pyrrolo[2,3-b]pyridine
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ≥ 33 mg/mL (~78.28 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.87 mg/mL (6.81 mM) (saturation unknown) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.87 mg/mL (6.81 mM) (saturation unknown) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (4.93 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: ≥ 2.08 mg/mL (4.93 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 5: ≥ 2.08 mg/mL (4.93 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3723 mL | 11.8613 mL | 23.7225 mL | |
| 5 mM | 0.4745 mL | 2.3723 mL | 4.7445 mL | |
| 10 mM | 0.2372 mL | 1.1861 mL | 2.3723 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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