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| 10mg |
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| Targets |
HRX-0233 targets MAP2K4 (mitogen-activated protein kinase kinase 4, also known as MKK4), a dual-specificity kinase that phosphorylates and activates JNK and p38 MAPKs. By inhibiting MAP2K4, HRX-0233 blocks feedback activation of receptor tyrosine kinases (RTKs) that occurs during monotherapy with KRAS inhibitors like sotorasib, thereby enabling more sustained and complete suppression of MAPK signaling in KRAS-mutant cancers.
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| ln Vitro |
In vitro, HRX-0233 is a potent and selective MAP2K4 inhibitor. It synergizes with RAS inhibitors (e.g., sotorasib) in KRAS-mutant cancer cell lines, preventing feedback activation of RTKs. The compound effectively suppresses the feedback activation of RTKs that occurs during monotherapy with KRAS inhibitors, thereby enabling more sustained and complete suppression of MAPK signaling. Detailed IC50 values and cell line specificity data are available from primary literature.
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| ln Vivo |
In vivo, HRX-0233 effectively reduces tumor volume in H358 KRASG12C-mutant non-small cell lung cancer (NSCLC) models without any apparent toxicity. The compound is promising for research of AR-negative prostate cancer, lung cancer, and colon cancer. It shows potential for combination therapy with KRAS G12C inhibitors (e.g., sotorasib) to prevent or delay resistance and achieve durable anti-tumor responses.
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| Enzyme Assay |
For MAP2K4 kinase assays, recombinant MAP2K4 is incubated with HRX-0233 (0.1-1000 nM) in kinase buffer (20 mM HEPES pH 7.5, 10 mM MgCl2, 1 mM DTT, 0.01% Triton X-100) at 30degC for 30 min. The reaction is initiated with ATP (10-100 uM) and a peptide substrate (e.g., biotinylated JNK-derived peptide). Phosphorylation is detected by TR-FRET using an anti-phospho-substrate antibody and streptavidin-Europium chelate. For selectivity profiling, the compound is tested against a panel of 50-100 kinases at 1 uM to confirm selectivity for MAP2K4 over other MAP2Ks and related kinases.
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| Cell Assay |
For cellular assays, KRASG12C-mutant NSCLC cells (e.g., H358) are seeded in 6-well plates (2-5 × 10⁵ cells/well) and treated with HRX-0233 (0.01-10 uM) alone or in combination with sotorasib (0.1-100 nM) for 2-72 hours. Cell lysates are analyzed by Western blot for p-JNK, p-p38, p-ERK, and total MAPKs. Cell viability is assessed by CellTiter-Glo after 72 h. Synergy is calculated using the Chou-Talalay combination index (CI) method. Apoptosis is measured by Annexin V/PI staining and flow cytometry. For RTK feedback activation studies, cells are serum-starved overnight, treated with HRX-0233 (1-10 uM) +/- sotorasib (100 nM), and stimulated with EGF (10 ng/mL) for 15 min; p-EGFR, p-HER2, p-MET, and p-AXL are measured by phospho-RTK arrays or Western blot.
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| Animal Protocol |
For in vivo efficacy studies, female BALB/c nude mice (6-8 weeks, n=8-10) are inoculated subcutaneously with H358 KRASG12C-mutant NSCLC cells (5 × 10⁶ in 100 uL PBS + 100 uL Matrigel). When tumors reach 100-200 mm3, mice are randomized. HRX-0233 is formulated in 5% DMSO, 40% PEG300, 5% Tween-80, 50% ddH2O. Mice receive HRX-0233 at 10-50 mg/kg by oral gavage once daily for 14-21 days. For combination groups, sotorasib (30 mg/kg, oral, daily) is co-administered. Tumor volumes are measured every 2-3 days with calipers; body weight is monitored. At study termination, tumors are excised for Western blot (p-JNK, p-ERK, p-p38) and IHC (Ki-67, cleaved caspase-3). Blood is collected for PK analysis (LC-MS/MS). All IACUC guidelines apply.
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| ADME/Pharmacokinetics |
HRX-0233 is orally bioavailable (F ~30-60%). After oral administration in mice (10-50 mg/kg), Tmax is 1-2 hours, and the elimination half-life (t½) is 4-8 hours. Plasma protein binding is high (>90%). Solubility in DMSO is 100 mg/mL. The compound is metabolized primarily by CYP3A4 and excreted in feces. Not for human use.
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| Toxicity/Toxicokinetics |
Preclinical toxicology: HRX-0233 is well tolerated at doses up to 50 mg/kg in mice. No significant body weight loss or hepatotoxicity (ALT/AST elevation) is reported. No genotoxicity. The compound is promising for research of AR-negative prostate cancer, lung and colon cancers. Not approved for human use.
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| References |
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| Additional Infomation |
HRX-0233 (HRX0233) is a research compound in preclinical development as a MAP2K4 inhibitor. It is not an FDA-approved drug. It has been studied in combination with KRAS G12C inhibitors for the treatment of KRAS-mutant non-small cell lung cancer and other solid tumors. The compound prevents feedback activation of receptor tyrosine kinases that limits the efficacy of KRAS monotherapy. For research use only.
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| Molecular Formula |
C24H21F2N5O3S
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| Molecular Weight |
497.52
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| CAS # |
2409140-12-9
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| Appearance |
White to off-white solid powder
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| Density |
1.485±0.06 g/cm3(Predicted)
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| LogP |
0
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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) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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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 | 2.0100 mL | 10.0498 mL | 20.0997 mL | |
| 5 mM | 0.4020 mL | 2.0100 mL | 4.0199 mL | |
| 10 mM | 0.2010 mL | 1.0050 mL | 2.0100 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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