| Size | Price | Stock | Qty |
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| 5mg |
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| 10mg |
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| 25mg |
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| 50mg |
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| 100mg |
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| 250mg |
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| Other Sizes |
Purity: ≥98%
| Targets |
MTH1 (IC50 = 5 nM)
The primary target of TH588 is MTH1 (MutT Homolog 1, also known as NUDT1), a member of the nudix hydrolase family. MTH1 is an enzyme that sanitizes the nucleotide pool by hydrolyzing oxidized dNTPs, such as 8-oxo-dGTP, to their monophosphate forms, preventing their incorporation into DNA. By doing so, MTH1 protects cells from the mutagenic and cytotoxic effects of oxidative DNA damage. Cancer cells often experience high levels of oxidative stress and upregulate MTH1 to survive. TH588 inhibits MTH1 with an IC50 of approximately 5 nM. This inhibition leads to the accumulation of oxidized dNTPs, which are then incorporated into DNA during replication, causing DNA damage and cell death. TH588 selectively kills cancer cells because they are more dependent on MTH1 for survival than normal cells, which have lower levels of oxidative stress. The compound's selectivity for MTH1 over other proteins is an important feature for its use as a research tool and as a potential therapeutic agent. |
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| ln Vitro |
TH588 selectively kill U2OS and other cancer cell lines with less toxic to several primary or immortalized cells. Additionally, TH588 causes DNA damage, which results in DNA repair and an ATM-p53-mediated death response in U2OS cells. [1]
In vitro, TH588 is a highly potent MTH1 inhibitor with an IC50 of approximately 5 nM. MTH1 inhibition by TH588 causes incorporation of oxidized dNTPs into DNA in cancer cells, leading to DNA damage and cytotoxicity. The compound selectively kills U2OS and other cancer cell lines with less toxicity to several primary or immortalized cells. TH588 also induces DNA damage and triggers an ATM-p53-mediated death response and DNA repair in U2OS cells. At a concentration of 100 µM, TH588 shows no relevant inhibition of other proteins tested, but at 10 µM, it shows some selectivity for other enzymes, GPCRs, kinases, ion channels, and transporters. The compound's in vitro activity is well-characterized and forms the basis for its use as a first-in-class MTH1 inhibitor. TH588 is a valuable tool for studying the role of MTH1 in cancer and for validating MTH1 as a drug target. |
| ln Vivo |
TH588 (30 mg/kg s.c.) inhibits MTH1 to slow the growth of tumors in mice with xenografts of the breast tumor MCF7 or the colorectal tumor SW480. TH588 (30 mg/kg s.c.) also slows the growth of tumors in mice bearing xenografts from patients with BRAFV600E mutations. [1]
In vivo, TH588 demonstrates antitumor activity in patient-derived mouse xenografts. MTH1 inhibition leads to therapeutic responses in vivo. The compound's in vivo efficacy is attributed to its ability to cause DNA damage and cell death in cancer cells. TH588 is a good chemical tool to exemplify the non-oncogene addiction concept for anticancer treatment. Further studies are needed to fully characterize the compound's in vivo pharmacokinetics and efficacy in different cancer models. The compound's selectivity for cancer cells over normal cells is a key advantage for its potential therapeutic use. |
| Enzyme Assay |
Cell-free enzyme assays with TH588 are performed using purified recombinant MTH1 (NUDT1) enzyme. The enzyme is incubated with oxidized dNTP substrates (e.g., 8-oxo-dGTP) and varying concentrations of TH588. Enzyme activity is measured by HPLC or mass spectrometry to determine IC50 values. These cell-free assays are essential for characterizing the potency and selectivity of TH588 as an MTH1 inhibitor. The compound's activity against other nudix hydrolases and 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 MTH1 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, cancer cell lines (e.g., U2OS, other cancer cell lines) are treated with TH588 at varying concentrations. Cell viability is assessed using MTT or CellTiter-Glo assays. DNA damage is measured by γ-H2AX staining. Apoptosis is evaluated by Annexin V staining and caspase activity assays. The compound's effects on cell proliferation and cell cycle progression are also assessed. These cellular assays are crucial for understanding the functional consequences of MTH1 inhibition and for validating the compound's activity as an MTH1 inhibitor. 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 TH588 in cancer research.
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| Animal Protocol |
SCID mice bearing SW480 xenografts or MCF-7 xenografts; NOD-SCID IL2Rγnull (NOG) mice bearing patient with BRAFV600E mutated xenografts
30 mg/kg, once daily s.c. In vivo efficacy of TH588 is evaluated in mouse xenograft models using patient-derived tumors. The compound is administered via intraperitoneal injection or oral gavage. Tumor growth inhibition, DNA damage markers, and survival are monitored. The compound's ability to inhibit tumor growth 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 TH588 as a therapeutic agent. |
| ADME/Pharmacokinetics |
Pharmacokinetic properties of TH588 including bioavailability, half-life, and tissue distribution are determined in preclinical studies. Parameters are evaluated following administration in rodents using LC-MS/MS analysis. The compound's bioavailability and half-life are important for determining the appropriate dosing regimen for in vivo studies. The compound's tissue distribution is also assessed to ensure that it reaches its target tissues. The pharmacokinetic data obtained from these studies are essential for designing appropriate dosing regimens and for interpreting the results of efficacy and toxicity studies.
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| Toxicity/Toxicokinetics |
Standard toxicology studies in rodents assess the safety profile of TH588. Acute and repeat-dose toxicity, organ histopathology, hematological parameters, and clinical chemistry are evaluated. The compound selectively kills cancer cells with less toxicity to primary or immortalized cells, suggesting a favorable safety profile. However, the compound's toxicity may include effects on tissues with high rates of cell proliferation. The compound is for research use only and has not been evaluated for human safety. Standard safety precautions should be followed when handling TH588, including the use of appropriate personal protective equipment and adherence to institutional safety guidelines.
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| References | |
| Additional Infomation |
TH588 (CAS 1609960-31-7) is a research compound for laboratory use only. It is a first-in-class, potent, and selective inhibitor of MTH1 (NUDT1) with an IC50 of approximately 5 nM. The compound selectively kills cancer cells with less toxicity to normal cells. TH588 is used to validate MTH1 as a drug target for anticancer treatment and to exemplify the non-oncogene addiction concept. It is not approved for human therapeutic use and is intended for research purposes only. The compound should be stored according to the manufacturer's recommendations, typically at -20°C, to ensure stability. When handling TH588, 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 |
C13H12CL2N4
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|---|---|
| Molecular Weight |
295.1672
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| Exact Mass |
294.043
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| Elemental Analysis |
C, 52.90; H, 4.10; Cl, 24.02; N, 18.98
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| CAS # |
1609960-31-7
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| Related CAS # |
TH588 hydrochloride;1640282-30-9
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| PubChem CID |
73389731
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| Appearance |
White to off-white solid powder
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| Density |
1.5±0.1 g/cm3
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| Boiling Point |
545.7±60.0 °C at 760 mmHg
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| Flash Point |
283.9±32.9 °C
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| Vapour Pressure |
0.0±1.5 mmHg at 25°C
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| Index of Refraction |
1.725
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| LogP |
3.85
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
19
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| Complexity |
313
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| Defined Atom Stereocenter Count |
0
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| SMILES |
ClC1C(=C([H])C([H])=C([H])C=1C1=C([H])C(=NC(N([H])[H])=N1)N([H])C1([H])C([H])([H])C1([H])[H])Cl
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| InChi Key |
PNMYJIOQIAEYQL-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C13H12Cl2N4/c14-9-3-1-2-8(12(9)15)10-6-11(17-7-4-5-7)19-13(16)18-10/h1-3,6-7H,4-5H2,(H3,16,17,18,19)
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| Chemical Name |
4-N-cyclopropyl-6-(2,3-dichlorophenyl)pyrimidine-2,4-diamine
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| Synonyms |
TH 588; TH588; TH-588
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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: 16~59 mg/mL (54.2~199.9 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (8.47 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 25.0 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: ≥ 2.5 mg/mL (8.47 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 25.0 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: ≥ 2.5 mg/mL (8.47 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 | 3.3879 mL | 16.9394 mL | 33.8788 mL | |
| 5 mM | 0.6776 mL | 3.3879 mL | 6.7758 mL | |
| 10 mM | 0.3388 mL | 1.6939 mL | 3.3879 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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