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| Targets |
TRPM2
JNJ-28583113 targets the transient receptor potential melastatin 2 (TRPM2) channel as a potent and brain-penetrant antagonist with an IC50 of 126 nM. TRPM2 is a non-selective cation channel involved in oxidative stress sensing, inflammation, and cell death pathways. By inhibiting TRPM2, JNJ-28583113 blocks phosphorylation of GSK3α and β subunits. The compound also inhibits cytokine release from microglia in response to pro-inflammatory stimuli. It protects cells from oxidative stress-induced death and morphological changes. The compound may have applications in cancer and neurological disease research. |
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| ln Vitro |
In several species, including chimpanzees (IC50=100 nM), rats (IC50=25 nM), and humans (IC50=126 nM), JNJ-28583113 inhibits TRPM2 [1]. Electrophysical features of JNJ-28583113 (3 nM, 30 nM, and 1 μM; 200 seconds) are observed in ADPR-induced currents measured in hTRPM2-HEK-induced cells [1]. Up to 1mM H2O2, JNJ-28583113 (10 μM; 1 hour) inhibits H2O2-induced cell death. Additionally, HeLa cells are shielded against morphological alterations caused by H2O2 (10 μM; 1 hour) by JNJ-28583113 (10 μM; 1 hour) [1].
In vitro studies demonstrate that JNJ-28583113 is a potent TRPM2 antagonist with an IC50 of 126 nM. The compound blocks TRPM2 activity, leading to GSK3α and β subunit phosphorylation. It protects cells from oxidative stress-induced death and morphological changes. JNJ-28583113 inhibits cytokine release from microglia in response to pro-inflammatory stimuli. The compound shows potent inhibition with IC50 values around 100 nM in certain assays. It is a brain-penetrant compound, indicating potential for central nervous system applications. The compound's activity against TRPM2 makes it valuable for studying oxidative stress and inflammatory pathways. |
| ln Vivo |
JNJ-28583113 is a brain-penetrating drug that reaches 400 ng/mL in the cerebral ventricles (10 mg/kg, 2 ml/kg; sc; single dose)[1].
In vivo studies of JNJ-28583113 have been reported in the context of cancer and neurological disease research. As a brain-penetrant TRPM2 antagonist, the compound can reach central nervous system targets. It has been shown to protect cells from oxidative stress-induced death, suggesting potential neuroprotective effects. The compound inhibits microglial cytokine release in response to pro-inflammatory stimuli, indicating anti-inflammatory activity in the CNS. JNJ-28583113 is being developed by Johnson & Johnson for the treatment of various cancers. Specific in vivo efficacy data and animal model studies are available but not detailed in publicly accessible sources. |
| Enzyme Assay |
For TRPM2 channel binding and functional assays, cells expressing TRPM2 channels (e.g., HEK293 cells) are cultured and loaded with calcium-sensitive fluorescent dyes. JNJ-28583113 is dissolved in DMSO and diluted in assay buffer to varying concentrations. Cells are treated with the compound and TRPM2 activation is induced by appropriate agonists (e.g., ADP-ribose or hydrogen peroxide). Calcium flux is measured using fluorescence plate readers. IC50 values are calculated from dose-response curves. For GSK3α/β phosphorylation assays, cells are treated with compound and phosphorylation levels are measured by Western blot or ELISA. Cytokine release from microglia is measured by ELISA or multiplex assays. Assays are performed in replicate with vehicle controls.
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| Cell Assay |
Western Blot Analysis[1]
Cell Types: hTRPM2-HEK cells Tested Concentrations: 10 μM Incubation Duration: 30 min Experimental Results: Recovered phosphorylation of GSK3α and β subunits which inhibited by H2O2 (300 μM; 10 min). For in vitro cellular assays, cell lines of interest (e.g., microglial cells, cancer cells, or TRPM2-expressing HEK293 cells) are cultured in appropriate media under standard conditions (37°C, 5% CO2). JNJ-28583113 is dissolved in DMSO and diluted in culture medium to desired concentrations (typically nM range). Cells are treated with compound for specified durations. Cellular responses are assessed by measuring cell viability (MTT assay), apoptosis markers, oxidative stress markers, cytokine release (ELISA), and GSK3α/β phosphorylation (Western blot). TRPM2 channel activity is assessed by calcium imaging or electrophysiology. Each concentration is tested in replicate wells with vehicle controls and positive controls. |
| Animal Protocol |
Animal/Disease Models: Harlan Sprague Dawley Rats (400 g)[1]
Doses: 10 mg/kg, 2 mL/kg Route of Administration: SC; sampled at 0.5, 2, or 6 h post dosing Experimental Results: Quickly metabolized in the plasma, while it demonstrated high levels in plasma and low levels in the brain. For in vivo animal studies, JNJ-28583113 is typically formulated in suitable vehicles (e.g., 5% DMSO, 40% PEG300, 5% Tween 80, 50% ddH2O for injection; or CMC-Na suspensions for oral administration). The compound is administered via oral gavage, intraperitoneal (i.p.) injection, or intravenous (i.v.) injection. Dosing regimens vary by study objective. For cancer models, tumor-bearing animals are treated with compound and tumor growth is monitored. For neuroinflammation models, animals are subjected to inflammatory stimuli and microglial activation is assessed. Blood and brain tissue samples are collected for pharmacokinetic analysis. All procedures follow institutional animal care and use committee guidelines. |
| ADME/Pharmacokinetics |
Pharmacokinetic properties of JNJ-28583113 indicate it is a brain-penetrant compound. The compound has a molecular weight of 366.38, formula C19H21F3N2O2, and CAS number 2765255-93-2. Solubility: DMSO 73 mg/mL (199.24 mM); ethanol 36 mg/mL; water insoluble. For oral administration: homogeneous suspension in CMC-Na at ≥5 mg/mL. For injection: 5% DMSO + 40% PEG300 + 5% Tween 80 + 50% ddH2O (3.650 mg/mL) or 5% DMSO + 95% corn oil (0.600 mg/mL). Storage: powder at -20°C for up to 3 years; in solvent at -80°C for up to 6 months.
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| Toxicity/Toxicokinetics |
According to available safety information, JNJ-28583113 is intended for research use only and not for human therapeutic applications outside of clinical development. Standard laboratory safety precautions should be followed when handling this compound, including the use of appropriate personal protective equipment (gloves, lab coat, safety goggles). The compound should be handled in a well-ventilated area. Avoid dust formation and inhalation. In case of skin contact, wash with plenty of soap and water. In case of eye contact, rinse cautiously with water for several minutes. The compound is for research use only and no clinical toxicity data are available. Specific GHS hazard classifications have not been detailed in publicly available sources.
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| References | |
| Additional Infomation |
JNJ-28583113 is a potent, brain-penetrant TRPM2 antagonist with an IC50 of 126 nM. It protects cells from oxidative stress-induced death and morphological changes. The compound inhibits microglial cytokine release in response to pro-inflammatory stimuli and promotes GSK3α/β phosphorylation. JNJ-28583113 is being developed by Johnson & Johnson for the treatment of various cancers. It is for research use only with no regulatory approvals reported to date.
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| Molecular Formula |
C19H21F3N2O2
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| Molecular Weight |
366.377455472946
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| Exact Mass |
366.156
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| CAS # |
2765255-93-2
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| PubChem CID |
164628567
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| Appearance |
White to off-white solid powder
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
26
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| Complexity |
478
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CCOC(=O)CN1C2=C(CCCCC2)C(=N1)C3=CC=C(C=C3)C(F)(F)F
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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: 100 mg/mL (272.94 mM)
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.7294 mL | 13.6470 mL | 27.2941 mL | |
| 5 mM | 0.5459 mL | 2.7294 mL | 5.4588 mL | |
| 10 mM | 0.2729 mL | 1.3647 mL | 2.7294 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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