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| Targets |
The primary target of TH1217 is dCTPase pyrophosphatase 1 (dCTPase), an enzyme that hydrolyzes dCTP to dCMP and pyrophosphate. By inhibiting dCTPase, TH1217 prevents the breakdown of dCTP, leading to an increase in intracellular dCTP levels. This elevation of dCTP competes with cytidine analogs, such as cytarabine (Ara-C), for incorporation into DNA during replication. The increased competition enhances the cytotoxic effects of these analogs in leukemia cells. The compound's inhibition of dCTPase is highly potent, with an IC50 of 47 nM. TH1217 is a selective inhibitor, meaning it specifically targets dCTPase without significantly affecting other enzymes. This selectivity is important for minimizing off-target effects and for accurately studying the role of dCTPase in cellular metabolism and cancer. The compound's ability to modulate SARS-CoV-2 interactors suggests that dCTPase may also play a role in viral replication, making TH1217 a potential antiviral agent.
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| ln Vitro |
TH1217 (compound 30) exhibits dCTPase inhibition, increases water solubility (>100 μM), and improves plasma stability (t4h=86%) in vitro [1]. The mouse microsomal half-life of TH1217 is 109 minutes, which is suitable [1]. Good cell permeability (8.66×10-6/1.30×10-3 cm/s) and CYP inhibitory action are demonstrated by TH1217 [1].
In vitro, TH1217 potently inhibits dCTPase with an IC50 of 47 nM. This inhibition leads to an increase in intracellular dCTP levels, which enhances the cytotoxicity of cytidine analogs in leukemia cells. The compound's in vitro activity is well-characterized and forms the basis for its use in cancer research. TH1217 enhances aqueous solubility (>100 μM) and improves plasma stability in vitro (t½ = 86%). It also presents suitable mouse microsomal half-lives (109 minutes). However, TH1217 is not stable in aqueous solution; it is recommended that fresh samples are prepared and used immediately. The compound's in vitro activity, combined with its favorable solubility and stability properties, makes it a valuable tool for studying the role of dCTPase in cancer and for developing new therapeutic strategies. Additionally, TH1217 can modulate SARS-CoV-2 interactors, suggesting possible anti-COVID-19 activity. |
| ln Vivo |
In vivo, TH1217 enhances the efficacy of cytidine analogs in leukemia models. By inhibiting dCTPase, the compound increases the intracellular concentration of dCTP, which competes with cytidine analogs for incorporation into DNA, thereby enhancing their cytotoxicity. In animal models of leukemia, TH1217 has been shown to potentiate the antitumor activity of cytarabine. The compound's in vivo efficacy is attributed to its ability to modulate dCTP levels and enhance the effects of cytidine analogs. Further studies are needed to fully characterize the compound's in vivo pharmacokinetics and efficacy in different cancer models. The compound's ability to modulate SARS-CoV-2 interactors also suggests potential antiviral activity in vivo.
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| Enzyme Assay |
Cell-free enzyme assays with TH1217 are performed using purified recombinant dCTPase pyrophosphatase 1. The enzyme is incubated with dCTP substrate and varying concentrations of TH1217. Pyrophosphate release is measured colorimetrically or by HPLC to determine the IC50 value. These cell-free assays are essential for characterizing the potency and selectivity of TH1217 as a dCTPase inhibitor. The compound's activity against other enzymes is assessed to determine its selectivity profile. The cell-free assay data provide a quantitative measure of the compound's inhibitory activity and are used to compare its potency with other dCTPase inhibitors. These data are also important for understanding the structure-activity relationships (SAR) of the compound and for guiding the design of more potent and selective inhibitors.
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| Cell Assay |
In cellular assays, leukemia cell lines are treated with TH1217 alone or in combination with cytidine analogs (e.g., cytarabine). Cell viability is assessed using MTT or CellTiter-Glo assays. Synergy between TH1217 and cytidine analogs is evaluated using combination index analysis. The compound's effects on intracellular dCTP levels are measured by HPLC or mass spectrometry. These cellular assays are crucial for understanding the functional consequences of dCTPase inhibition and for validating the compound's activity as a sensitizer to cytidine analogs. The compound's potency in cellular systems is consistent with its activity in cell-free assays. The results from these assays provide valuable information for the use of TH1217 in cancer research.
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| Animal Protocol |
In vivo efficacy of TH1217 is evaluated in mouse xenograft models of leukemia. The compound is administered alone or in combination with cytidine analogs. Tumor growth inhibition, survival, and biomarker analysis are performed to assess therapeutic benefit. The compound's ability to potentiate the antitumor activity of cytarabine is a key measure of its efficacy. These in vivo studies are essential for confirming the compound's efficacy in a physiologically relevant context and for guiding the development of TH1217 as a therapeutic agent.
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| ADME/Pharmacokinetics |
TH1217 is not stable in aqueous solution; fresh samples should be prepared and used immediately. Pharmacokinetic parameters are determined following administration in preclinical models, with special attention to stability and formulation conditions. The compound's bioavailability, half-life, and tissue distribution are assessed. The compound's instability in aqueous solution necessitates careful handling and formulation to ensure accurate dosing and reproducible results.
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| Toxicity/Toxicokinetics |
Standard toxicology studies assess the safety of TH1217 in animal models. Parameters evaluated include body weight, clinical observations, hematology, clinical chemistry, and organ histopathology. The compound is for research use only and has not been evaluated for human safety. Standard safety precautions should be followed when handling TH1217, including the use of appropriate personal protective equipment and adherence to institutional safety guidelines.
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| References | |
| Additional Infomation |
TH1217 (ZINC1775962367, CAS 1862212-48-3) is a research compound for laboratory use only. It is a potent and selective inhibitor of dCTPase pyrophosphatase 1 (dCTPase) with an IC50 of 47 nM. The compound enhances the cytotoxic effects of cytidine analogs in leukemia cells and may modulate SARS-CoV-2 interactors. It enhances aqueous solubility (>100 μM) and improves plasma stability (t½ = 86%). TH1217 is not stable in aqueous solution; fresh samples should be prepared and used immediately. The compound is not approved for human therapeutic use and is intended for research purposes only. It should be stored according to the manufacturer's recommendations, typically at -20°C, to ensure stability. When handling TH1217, researchers should follow standard safety protocols for handling chemical reagents, including the use of appropriate personal protective equipment and working in a well-ventilated area.
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| Molecular Formula |
C20H17BCL2N4O6
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| Molecular Weight |
491.08918261528
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| Exact Mass |
490.06
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| Elemental Analysis |
C, 48.92; H, 3.49; B, 2.20; Cl, 14.44; N, 11.41; O, 19.55
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| CAS # |
1862212-48-3
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| PubChem CID |
137919863
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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 |
8
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
33
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| Complexity |
833
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| Defined Atom Stereocenter Count |
0
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| SMILES |
[B-]12([N+](CC(=O)O1)(CC(=O)O2)C)C3=CC=C(C=C3)CN4C(=NC5=C(C(=C(C=C54)Cl)Cl)[N+](=O)[O-])C
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| InChi Key |
HWFRCQHNILGMLL-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C20H17BCl2N4O6/c1-11-24-19-15(7-14(22)18(23)20(19)26(30)31)25(11)8-12-3-5-13(6-4-12)21-27(2,9-16(28)32-21)10-17(29)33-21/h3-7H,8-10H2,1-2H3
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| Chemical Name |
1-[4-[(5,6-dichloro-2-methyl-4-nitrobenzimidazol-1-yl)methyl]phenyl]-5-methyl-2,8-dioxa-5-azonia-1-boranuidabicyclo[3.3.0]octane-3,7-dione
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| Synonyms |
TH 1217; TH1217; TH-1217; ZINC1775962367; ZINC-1775962367; ZINC1775962367;
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| HS Tariff Code |
2934.99.03.00
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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 (~254.54 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 | 2.0363 mL | 10.1814 mL | 20.3629 mL | |
| 5 mM | 0.4073 mL | 2.0363 mL | 4.0726 mL | |
| 10 mM | 0.2036 mL | 1.0181 mL | 2.0363 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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