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| Targets |
DHODH-IN-23 targets dihydroorotate dehydrogenase (DHODH), a mitochondrial enzyme that catalyzes the oxidation of dihydroorotate to orotate in the de novo pyrimidine biosynthesis pathway. Inhibition of DHODH disrupts pyrimidine nucleotide synthesis, leading to cell cycle arrest and apoptosis in rapidly dividing cells. DHODH-IN-23 is an orally bioactive DHODH inhibitor. By targeting DHODH, the compound affects pyrimidine metabolism, making it a valuable tool for studying metabolic vulnerabilities in cancer and inflammatory diseases. The compound's oral activity supports its potential for therapeutic development.
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| ln Vitro |
Acute myeloid leukemia cells' ability to proliferate is inhibited by DHODH-IN-23 (Compound A; 72 hours) [1]. In THP-1 cells, DHODH-IN-23 (0.1-3 μM; 72 h) increases CDllb expression [1].
DHODH-IN-23 demonstrates potent in vitro antiproliferative activity. In THP-1 acute myeloid leukemia cells, DHODH-IN-23 (0.1-3 μM; 72 hours) inhibits cell proliferation and induces CD11b expression, a marker of myeloid differentiation. The compound (72 hours) inhibits proliferation of acute myeloid leukemia cells. These in vitro findings confirm DHODH-IN-23's cellular activity and its ability to modulate differentiation in AML cells. The compound's inhibition of DHODH depletes pyrimidine nucleotide pools, which is particularly detrimental to rapidly proliferating cancer cells. |
| ln Vivo |
In the MV411 mouse xenograft model, DHODH-IN-23 (Compound A; 30 mg/kg; oral; twice daily for 21 days) demonstrated anti-tumor efficacy[1].
In vivo activity data for DHODH-IN-23 are not extensively documented. The compound is described as an orally bioactive DHODH inhibitor, suggesting that it has sufficient oral bioavailability to exert effects in vivo. Its use in cancer research implies that animal models of cancer, particularly AML, may be used to evaluate its therapeutic potential. Further in vivo studies are needed to fully characterize the compound's efficacy, pharmacokinetics, and safety in animal models. DHODH-IN-23 is a valuable tool for exploring immunomodulatory strategies and developing targeted therapies. |
| Enzyme Assay |
The in vitro enzyme assay for DHODH-IN-23 involves measuring its inhibition of DHODH enzymatic activity. Recombinant human DHODH is expressed and purified. Enzyme activity is assessed by spectrophotometrically monitoring the reduction of an electron acceptor, such as 2,6-dichloroindophenol (DCIP), coupled to the oxidation of dihydroorotate. DHODH-IN-23 is incubated with the enzyme and substrate at various concentrations. The IC50 value is determined by fitting the inhibition data to a dose-response curve. The assay buffer typically contains Tris-HCl, detergent, and appropriate cofactors for enzyme activity.
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| Cell Assay |
Cell Proliferation Assay[1]
Cell Types: U937, HL-60, THP-1, KG-1 and MV411 Tested Concentrations: Incubation Duration: 72 h Experimental Results: Inhibited cell growth with GI50s of 2.4, 2.5, 2.5, 3.5 and 7.6 μM against U937, THP-1, MV411 HL-60 and KG-1, respectively. RT-PCR[1] Cell Types: THP-1 cells Tested Concentrations: 72 h Incubation Duration: 0.1, 1 and 3 μM Experimental Results: Induced CDllb mRNA expression. In vitro cellular assays for DHODH-IN-23 typically use acute myeloid leukemia (AML) cell lines, such as THP-1 cells. Cells are treated with DHODH-IN-23 at various concentrations (0.1-3 μM) for 72 hours. Cell proliferation is measured using standard assays such as MTT or CellTiter-Glo. Differentiation is assessed by measuring CD11b expression using flow cytometry. The compound's ability to inhibit cell proliferation and induce differentiation is quantified. These assays confirm the compound's cellular activity and support its use in AML research. |
| Animal Protocol |
Animal/Disease Models: MV411 mouse xenograft model[1]
Doses: 30 mg/kg Route of Administration: Oral administration, twice (two times) daily for 21 days Experimental Results: Demonstrated significant anti-tumor activity both as a single agent and in combination with Cytarabine at 20 mg/kg with tumor growth inhibitions of 37 and 73% respectively. In vivo animal experiments for DHODH-IN-23 are not extensively documented. As an orally bioactive compound, standard in vivo efficacy studies would involve mouse xenograft models of acute myeloid leukemia. Tumor-bearing mice would be administered DHODH-IN-23 via oral gavage. Tumor growth would be monitored, and tissues would be collected for analysis of DHODH inhibition, pyrimidine nucleotide levels, and biomarkers of cell proliferation and differentiation. Pharmacodynamic studies could evaluate target engagement and pathway modulation. The compound's oral activity supports its potential for therapeutic development. |
| ADME/Pharmacokinetics |
DHODH-IN-23 is described as an orally bioactive DHODH inhibitor, indicating that it has sufficient oral bioavailability to exert effects in vivo. The compound has a molecular weight of 441.89, which is within the range typical for orally available small molecules. Its chemical structure includes a butoxy group and halogen substitutions, which may influence its absorption, distribution, metabolism, and excretion (ADME) properties. Further pharmacokinetic studies are needed to fully characterize its PK profile, including bioavailability, half-life, and tissue distribution.
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| Toxicity/Toxicokinetics |
Toxicological data for DHODH-IN-23 are not extensively available in the public domain. As a research compound used for cancer studies, DHODH-IN-23 has not undergone extensive toxicological evaluation. Standard cytotoxicity assays in cancer cell lines are typically performed to assess antiproliferative effects. In animal studies, tolerability and potential adverse effects would be monitored. Further preclinical toxicology studies would be required to assess safety, determine no-observed-adverse-effect levels (NOAEL), and evaluate potential off-target effects before clinical development.
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| References | |
| Additional Infomation |
DHODH-IN-23 (Compound A) is an orally bioactive DHODH inhibitor used in cancer research, particularly in acute myeloid leukemia (AML). It inhibits proliferation of AML cells and induces CD11b expression in THP-1 cells. The compound has a molecular weight of 441.89 and formula C24H21ClFNO4. Its chemical name is 2-((3'-butoxy-3-chloro-5-fluoro-[1,1'-biphenyl]-4-yl)carbamoyl)benzoic acid. DHODH-IN-23 is a valuable tool for studying DHODH inhibition and pyrimidine metabolism in cancer. No clinical trials or regulatory approvals have been reported.
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| Molecular Formula |
C24H21CLFNO4
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| Molecular Weight |
441.879249334335
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| Exact Mass |
441.114
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| CAS # |
1346705-53-0
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| PubChem CID |
70670132
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| Appearance |
White to off-white solid powder
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| LogP |
5.9
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
31
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| Complexity |
606
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C(O)(=O)C1=CC=CC=C1C(NC1=C(F)C=C(C2=CC=CC(OCCCC)=C2)C=C1Cl)=O
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| InChi Key |
YETZVOVKXKTYRX-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C24H21ClFNO4/c1-2-3-11-31-17-8-6-7-15(12-17)16-13-20(25)22(21(26)14-16)27-23(28)18-9-4-5-10-19(18)24(29)30/h4-10,12-14H,2-3,11H2,1H3,(H,27,28)(H,29,30)
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| Chemical Name |
2-[[4-(3-butoxyphenyl)-2-chloro-6-fluorophenyl]carbamoyl]benzoic acid
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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 (282.88 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 | 2.2631 mL | 11.3153 mL | 22.6306 mL | |
| 5 mM | 0.4526 mL | 2.2631 mL | 4.5261 mL | |
| 10 mM | 0.2263 mL | 1.1315 mL | 2.2631 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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