TH588 HCl (TH-588; TH 588), the hydrochloride salt of TH-588, is a potent inhibitor of human 7,8-Dihydro-8-oxoguaninetriphosphatase MTH1 (NUDT1) with anti-cancer activity. It inhibits MTH1 with an IC50 of 5 nM and has good metabolic stability. Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. TH588 a first-in-class nudix hydrolase family inhibitor that potently and selectively engages and inhibits the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitor binds in the active site of MTH1.
Physicochemical Properties
| Molecular Formula | C13H13CL3N4 |
| Molecular Weight | 331.62811923027 |
| Exact Mass | 330.02 |
| CAS # | 1640282-30-9 |
| Related CAS # | TH588;1609960-31-7 |
| PubChem CID | 91826507 |
| Appearance | Typically exists as solid at room temperature |
| Hydrogen Bond Donor Count | 3 |
| Hydrogen Bond Acceptor Count | 4 |
| Rotatable Bond Count | 3 |
| Heavy Atom Count | 20 |
| Complexity | 313 |
| Defined Atom Stereocenter Count | 0 |
| SMILES | NC1N=C(NC2CC2)C=C(C2C(Cl)=C(Cl)C=CC=2)N=1.[H]Cl |
| InChi Key | FBHMEHNWFXCSKE-UHFFFAOYSA-N |
| InChi Code | InChI=1S/C13H12Cl2N4.ClH/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);1H |
| Chemical Name | 4-N-cyclopropyl-6-(2,3-dichlorophenyl)pyrimidine-2,4-diamine;hydrochloride |
| HS Tariff Code | 2934.99.9001 |
| 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) |
Biological Activity
| ln Vitro | With IC50 values of 1.38, 0.83, 1.03, 1.08, 1.72, and 0.8 μM, TH588 (2-10μM; 7-10 days) effectively and selectively kills HeLa, MDA-MB-231, MCF-7, SW480, and SW620 cells [1]. |
| ln Vivo | In the SW480 xenograft cancer model, TH588 (30 mg/kg; subcutaneous injection; once daily for 35 days) inhibits the growth of tumors [1]. |
| Cell Assay |
Cell viability assay[1] Cell Types: U2OS, HeLa, MDA-MB-231, MCF-7, SW480, SW620, VH10, HDFn Cell Tested Concentrations: 2, 4, 6, 8, 10 μM Incubation Duration: 7–10 days Experimental Results: Selectively and effectively kill U2OS, HeLa, MDA-MB-231, MCF-7, SW480 and SW620 cells, with IC50 of 1.38, 0.83, 1.03, 1.08, 1.72, 0.8 μM respectively, but it is toxic to several primary cells. smaller. or immortalized cells. |
| Animal Protocol |
Animal/Disease Models: 5-6 weeks female SCID (severe combined immunodeficient) mouse (SW480 xenograft cancer model) [1] Doses: 30 mg/kg Route of Administration: subcutaneous injection; one time/day for 35 days Experimental Results: SW480 xenograft cancer model tumor growth was diminished. |
| References | [1]. Gad H, et al. MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool. Nature. 2014 Apr 10;508(7495):215-21. |
Solubility Data
| 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 |
| 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 (e.g. IP/IV/IM/SC) Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline) *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). 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)] *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. Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline) Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline) Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline) Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil) Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL 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). Oral Formulation 3: Dissolved in PEG400 Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose Oral Formulation 6: Mixing with food powders Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.0154 mL | 15.0770 mL | 30.1541 mL | |
| 5 mM | 0.6031 mL | 3.0154 mL | 6.0308 mL | |
| 10 mM | 0.3015 mL | 1.5077 mL | 3.0154 mL |