TH588 (TH-588) is a novel and highly potent inhibitor of human 7,8-Dihydro-8-oxoguaninetriphosphatase MTH1 (NUDT1) with antitumor activity. It exhibits good metabolic stability and has an IC50 of 5 nM for inhibiting MTH1. Cancers have abnormal redox regulation, which leads to the production of reactive oxygen species, which harms both free dNTPs and DNA. To stop damaged bases from being incorporated during DNA replication, the MTH1 protein sanitizes oxidized dNTP pools. The MTH1 protein in cells is powerfully and specifically engaged and inhibited by TH588, a first-in-class nudix hydrolase family inhibitor. The inhibitor binds to MTH1's active site, as shown by protein co-crystal structures.
Physicochemical Properties
| Molecular Formula | C13H12CL2N4 |
| Molecular Weight | 295.1672 |
| Exact Mass | 294.043 |
| Elemental Analysis | C, 52.90; H, 4.10; Cl, 24.02; N, 18.98 |
| CAS # | 1609960-31-7 |
| Related CAS # | TH588 hydrochloride;1640282-30-9 |
| PubChem CID | 73389731 |
| Appearance | White to off-white solid powder |
| Density | 1.5±0.1 g/cm3 |
| Boiling Point | 545.7±60.0 °C at 760 mmHg |
| Flash Point | 283.9±32.9 °C |
| Vapour Pressure | 0.0±1.5 mmHg at 25°C |
| Index of Refraction | 1.725 |
| LogP | 3.85 |
| Hydrogen Bond Donor Count | 2 |
| Hydrogen Bond Acceptor Count | 4 |
| Rotatable Bond Count | 3 |
| Heavy Atom Count | 19 |
| Complexity | 313 |
| Defined Atom Stereocenter Count | 0 |
| 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 |
| InChi Key | PNMYJIOQIAEYQL-UHFFFAOYSA-N |
| 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) |
| Chemical Name | 4-N-cyclopropyl-6-(2,3-dichlorophenyl)pyrimidine-2,4-diamine |
| Synonyms | TH 588; TH588; TH-588 |
| 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
| Targets | MTH1 (IC50 = 5 nM) |
| 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] |
| 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] |
| 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. |
| References |
[1]. MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool. Nature. 2014 Apr 10;508(7495):215-21. |
Solubility Data
| Solubility (In Vitro) | DMSO: 16~59 mg/mL (54.2~199.9 mM) |
| 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. 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. 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 corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| 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 |