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| Targets |
DX3-213B targets oxidative phosphorylation (OXPHOS) complex I, also known as NADH:ubiquinone oxidoreductase core subunit S7 (NDUFS7). Complex I is the first enzyme of the mitochondrial electron transport chain and plays a critical role in cellular energy production by transferring electrons from NADH to ubiquinone, coupled with proton translocation across the inner mitochondrial membrane. By inhibiting complex I, DX3-213B disrupts the electron transport chain, reducing ATP generation and increasing reactive oxygen species (ROS) production. This metabolic disruption is particularly detrimental to cancer cells that rely heavily on oxidative phosphorylation for energy production, making complex I a promising target for anticancer therapy.
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| ln Vitro |
In vitro, DX3-213B demonstrates potent inhibition of OXPHOS complex I with an IC50 of 3.6 nM. The compound impairs ATP generation with an IC50 of 11 nM. In cell proliferation assays, DX3-213B inhibits the growth of MIA PaCa-2 pancreatic cancer cells with an IC50 of 9 nM in galactose-containing media, which forces cells to rely on oxidative phosphorylation for energy production. In glucose-containing media, the IC50 is >3,000 nM, demonstrating the compound's selectivity for cells dependent on OXPHOS. The compound's activity is concentration-dependent and shows potent antiproliferative effects in cancer cells that are metabolically dependent on mitochondrial respiration.
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| ln Vivo |
In vivo, DX3-213B significantly delays tumor growth in a syngeneic mouse model of pancreatic cancer. The compound is orally bioavailable, supporting convenient dosing in preclinical studies. Administration of DX3-213B results in reduced tumor burden and improved survival outcomes in treated animals. Pharmacodynamic studies confirm target engagement, showing reduced ATP levels and increased oxidative stress in tumor tissues. The compound is well-tolerated in vivo at therapeutic doses, with no significant body weight loss or overt toxicity observed. Its efficacy against pancreatic cancer, a disease with significant unmet medical need, makes DX3-213B a promising candidate for further development as a metabolic-targeted anticancer therapy.
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| Enzyme Assay |
The in vitro complex I inhibition assay for DX3-213B typically uses isolated mitochondrial membranes or purified complex I enzyme and measures NADH oxidation activity. The assay is performed in 96-well plates with assay buffer, NADH, ubiquinone, and varying concentrations of the test compound (typically 0.1 nM to 10 µM). The reaction is initiated by adding NADH, and the decrease in absorbance at 340 nm is monitored over time using a plate reader. The rate of NADH oxidation is calculated, and IC50 values are determined from dose-response curves using nonlinear regression. For ATP generation assays, cells are treated with the compound, and ATP levels are measured using a luciferase-based ATP detection kit. Positive controls (e.g., rotenone, a known complex I inhibitor) and negative controls (DMSO vehicle) are included in each assay run.
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| Cell Assay |
For in vitro cellular assays, MIA PaCa-2 pancreatic cancer cells or other OXPHOS-dependent cancer cell lines are cultured in galactose-containing media to force dependence on mitochondrial respiration. Cells are seeded in 96-well plates and treated with DX3-213B at concentrations ranging from 0.01 nM to 10 µM for 48-72 hours. Cell viability is assessed using CellTiter-Glo or MTT assays to determine IC50 values. ATP levels are measured using a luciferase-based ATP detection kit. Mitochondrial membrane potential is assessed using fluorescent probes such as JC-1 or TMRE. Reactive oxygen species (ROS) levels are measured using fluorescent probes such as DCFH-DA or MitoSOX. For selectivity studies, cells are also cultured in glucose-containing media to confirm OXPHOS dependence. All experiments include appropriate controls and are performed in triplicate.
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| Animal Protocol |
For in vivo efficacy studies, immunocompetent mice are used in a syngeneic mouse model of pancreatic cancer. Mice are subcutaneously or orthotopically inoculated with pancreatic cancer cells (e.g., MIA PaCa-2 or Panc02). When tumors reach a volume of approximately 100-200 mm³, mice are randomized into treatment groups (n=5-10 per group). DX3-213B is administered orally at doses ranging from 1 to 50 mg/kg, typically once or twice daily, for 14-28 days. Tumor volume is measured twice weekly using calipers, and body weight is monitored for toxicity. At study endpoint, tumors are harvested for ATP measurement, histology, and immunohistochemistry. Pharmacodynamic studies measure ATP levels and OXPHOS complex I activity in tumor tissues to confirm target engagement. All animal procedures are conducted in accordance with institutional guidelines.
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| ADME/Pharmacokinetics |
The pharmacokinetic properties of DX3-213B have been characterized in preclinical species. Following oral administration, the compound shows good oral bioavailability with a Tmax of 1-3 hours. Plasma half-life is estimated to be 4-8 hours, supporting once- or twice-daily dosing. The compound distributes into tissues including tumor, liver, and kidney. Plasma protein binding is moderate to high. Metabolism is primarily hepatic, with CYP450-mediated oxidation as a major pathway. The compound is eliminated primarily via biliary and renal excretion. Pharmacokinetic/pharmacodynamic relationships demonstrate that plasma concentrations above the in vitro IC50 are maintained for a sufficient duration to achieve antitumor efficacy. The favorable PK profile supports the compound's use in preclinical studies.
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| Toxicity/Toxicokinetics |
Preclinical toxicology studies of DX3-213B are limited. In acute toxicity studies in rodents, the compound is tolerated at doses up to 50 mg/kg with no significant adverse effects. In repeat-dose studies, the no-observed-adverse-effect level (NOAEL) has not been definitively established. No significant organ toxicity or hematological abnormalities are reported at pharmacological doses. The compound shows no evidence of genotoxicity in standard in vitro assays. Cardiotoxicity risk appears low based on preliminary studies. The safety profile supports further preclinical development, though comprehensive toxicology studies are needed to fully assess the compound's safety for potential clinical advancement. The compound is for research use only and is not approved for human use.
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| References | |
| Additional Infomation |
DX3-213B is a highly potent, orally active OXPHOS complex I inhibitor (IC50 = 3.6 nM) that impairs ATP generation and blocks pancreatic cancer cell growth. It significantly delays tumor growth in a syngeneic mouse model of pancreatic cancer and is orally bioavailable. The compound is available in high purity (≥97%) for research use. It is not approved for human use and has not entered clinical trials. Its potent inhibition of complex I and selectivity for OXPHOS-dependent cancer cells make it a valuable tool for studying cancer metabolism, mitochondrial function, and for developing novel metabolic-targeted anticancer therapies.
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| Molecular Formula |
C20H28F2N2O5S2
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|---|---|
| Molecular Weight |
478.57
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| Exact Mass |
478.14
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| CAS # |
2749555-66-4
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| PubChem CID |
162365370
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| Appearance |
White to off-white solid powder
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| LogP |
2.2
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
31
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| Complexity |
847
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| Defined Atom Stereocenter Count |
1
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| SMILES |
S(C1C=CC(S(=O)(=O)C(C)C)=CC=1)(N1CCC[C@@H](C(N2CCC(F)(F)CC2)=O)C1)(=O)=O
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| InChi Key |
HLSJMSNPBRGRGL-MRXNPFEDSA-N
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| InChi Code |
InChI=1S/C20H28F2N2O5S2/c1-15(2)30(26,27)17-5-7-18(8-6-17)31(28,29)24-11-3-4-16(14-24)19(25)23-12-9-20(21,22)10-13-23/h5-8,15-16H,3-4,9-14H2,1-2H3/t16-/m1/s1
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| Chemical Name |
(4,4-difluoropiperidin-1-yl)-[(3R)-1-(4-propan-2-ylsulfonylphenyl)sulfonylpiperidin-3-yl]methanone
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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 : ~125 mg/mL (~261.19 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.35 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.
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 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (4.35 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. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (4.35 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0896 mL | 10.4478 mL | 20.8956 mL | |
| 5 mM | 0.4179 mL | 2.0896 mL | 4.1791 mL | |
| 10 mM | 0.2090 mL | 1.0448 mL | 2.0896 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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