| Size | Price | Stock | Qty |
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| 5mg |
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| 25mg |
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Purity: ≥98%
TH287 is a potent and selective MTH1 (NUDT1) inhibitor with IC50 of 0.8 nM. TH287 selectively and efficiently kills U2OS and other cancer cell lines while being less toxic to many primary or immortalized cells, and it causes oxidative DNA damage. In U2OS and other cancer cell lines, TH287 treatment selectively and effectively kills cancer cells while being less toxic to some primary or immortalized cells. Increase in 8-oxodG in DNA is observed in U2OS cells treated with TH287. In U2OS cells, the MTH1 inhibitor TH287 causes DNA damage, activates an ATM-p53-mediated death response, and causes DNA repair.
| Targets |
MTH1 (IC50 = 0.8 nM)
TH287 targets MutT homolog 1 (MTH1, NUDT1) (IC50 = 0.8 nM for enzymatic inhibition; Ki = 0.5 nM) [1] |
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| ln Vitro |
TH287 (1-10 μM; 24 h) selectively and efficiently destroys U2OS and other cancer cell lines, but is considerably less toxic to several primary or immortalized cells[1].
TH287 potently inhibited MTH1 enzymatic activity, preventing hydrolysis of oxidized dNTPs (8-oxo-dGTP, 2-OH-dATP) with >95% inhibition at 10 nM [1] TH287 exhibited antiproliferative activity against diverse cancer cell lines: IC50 = 1.2 μM (A549 lung cancer), IC50 = 0.9 μM (HCT116 colon cancer), IC50 = 1.5 μM (MDA-MB-231 breast cancer), IC50 = 0.7 μM (K562 leukemia) [1] TH287 (2 μM, 48 hours) induced accumulation of oxidized dNTPs in cancer cells (8-oxo-dGTP levels increased by 3.2-fold), leading to DNA oxidative damage (γH2AX foci increased by 4.5-fold) [1] TH287 (1 μM, 72 hours) induced apoptosis in cancer cells, with Annexin V-positive cells reaching 52% and caspase-3/7 activity elevated by 3.8-fold [1] TH287 showed minimal toxicity to normal human fibroblasts (IC50 > 20 μM), with 15–25-fold selectivity for cancer cells [1] |
| ln Vivo |
In mice, TH287 (5 mg/kg; i.p.) has a Cmax of 0.82 M and a tmax of 0.5 h[2].
TH287 (25 mg/kg/day, intraperitoneal injection for 14 days) inhibited HCT116 colon cancer xenograft growth in nude mice by 68%, with no significant body weight loss (<5% change) [1] TH287 (15 mg/kg/day, oral gavage for 21 days) reduced A549 lung cancer xenograft volume by 62% in BALB/c nude mice, accompanied by increased γH2AX expression in tumor tissues [1] TH287 (20 mg/kg, intravenous injection) in C57BL/6 mice showed rapid distribution to tumor tissues (tumor/plasma ratio = 5.1 at 1 hour post-administration) [2] |
| Enzyme Assay |
MTH1 enzymatic activity assay: Recombinant MTH1 protein was incubated with TH287 (0.01–100 nM) and fluorescently labeled 8-oxo-dGTP substrate in reaction buffer; after 30 minutes at 37°C, hydrolyzed products were separated by HPLC, and fluorescence intensity was measured to calculate inhibition rate and IC50 [1]
Surface Plasmon Resonance (SPR) assay: MTH1 protein was immobilized on a sensor chip; TH287 (0.1–50 nM) was injected at a constant flow rate, and binding affinity (Ki) was determined by analyzing sensorgrams with steady-state affinity models [1] |
| Cell Assay |
In U2OS and other cancer cell lines, TH287 treatment selectively and effectively kill cancer cells with less toxic to some primary or immortalized cells. Increase in 8-oxodG in DNA is seen in U2OS cells treated with TH287. In U2OS cells, the MTH1 inhibitor TH287 causes DNA damage that prompts DNA repair and an ATM-p53-mediated death response.
Antiproliferation assay: Cancer cells and normal fibroblasts were seeded in 96-well plates (5×10³ cells/well) and treated with TH287 (0.1–50 μM) for 72 hours; cell viability was assessed by MTT assay (absorbance at 570 nm), and IC50 values were calculated [1] Oxidized dNTP accumulation assay: HCT116 cells were treated with TH287 (0.5–5 μM) for 48 hours; intracellular dNTPs were extracted, and 8-oxo-dGTP/2-OH-dATP levels were quantified by LC-MS/MS [1] DNA damage assay: A549 cells were treated with TH287 (0.5–2 μM) for 24 hours, fixed and immunostained with anti-γH2AX antibody; γH2AX foci were counted under fluorescence microscope [1] Apoptosis assay: K562 cells were treated with TH287 (0.5–3 μM) for 72 hours, stained with Annexin V-FITC/PI, and apoptotic cells were analyzed by flow cytometry; caspase-3/7 activity was detected by luminescent assay with specific substrates [1] |
| Animal Protocol |
Dissolved in 1% DMSO, 10% ethanol, 10% Chremophore EL and 10% Tween-80 and diluted with PBS; 5 mg/kg; i.p. injection.
C57Bl/6 mice Colon cancer xenograft model: Nude mice (6–8 weeks old) were subcutaneously injected with 2×10⁶ HCT116 cells; when tumors reached 120 mm³, mice were randomly divided into control and treatment groups; treatment group received TH287 (25 mg/kg/day, dissolved in 10% DMSO + 90% saline) via intraperitoneal injection for 14 days, control group received vehicle; tumor volume and body weight were measured every 2 days [1] Lung cancer xenograft model: BALB/c nude mice were subcutaneously implanted with 1×10⁷ A549 cells; tumors were allowed to grow to 100 mm³, then mice were administered TH287 (15 mg/kg/day, dissolved in 0.5% carboxymethylcellulose sodium) via oral gavage for 21 days; tumor tissues were collected for γH2AX expression analysis [1] Pharmacokinetic model: C57BL/6 mice (20–25 g) were administered TH287 (20 mg/kg, dissolved in PBS) via intravenous injection; blood samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours post-administration; plasma drug concentration was detected by UHPLC-MS/MS [2] |
| ADME/Pharmacokinetics |
After intravenous injection of TH287 (20 mg/kg) into mice, the peak plasma concentration (Cmax) was 8.3 μg/mL, the area under the curve (AUC₀₋₂₄h) was 25.6 μg·h/mL, and the elimination half-life (t1/2) was 3.7 h [2]. TH287 was widely distributed in the liver (tissue/plasma ratio of 6.2 at 2 h), tumors, and kidneys, but had low brain permeability (brain/plasma ratio of 0.2) [2]. The bioavailability of TH287 in mice after oral administration was approximately 22%, which was due to partial first-pass metabolism [1]. TH287 was metabolized in the liver via cytochrome P450-mediated oxidative metabolism, with the main metabolites excreted in feces (65%) and urine (28%) within 48 hours [2].
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| Toxicity/Toxicokinetics |
TH287 showed low acute toxicity in mice: intraperitoneal LD50 = 180 mg/kg, oral LD50 = 350 mg/kg [1]
Long-term administration to mice (25 mg/kg/day for 28 days) did not cause significant changes in serum ALT, AST, BUN or creatinine levels, indicating that it has no obvious toxicity [1] TH287 had a plasma protein binding rate of 92% in human plasma and 89% in mouse plasma [2] No significant drug interactions with major CYP450 enzymes were observed in in vitro experiments [2] |
| References |
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| Additional Infomation |
TH287 is a potent and selective small molecule MTH1 inhibitor, MTH1 being a nucleotide pool purifying enzyme [1][2]. It exerts its antitumor effect by inhibiting MTH1-mediated oxidative dNTP hydrolysis, leading to the incorporation of damaged nucleotides into DNA, inducing oxidative DNA damage, and ultimately causing apoptosis in cancer cells [1]. TH287 has broad-spectrum antitumor activity against a variety of cancer types, including solid tumors and hematologic malignancies [1]. The drug is more selective for cancer cells than for normal cells, which is attributed to the increased dependence of cancer cells on MTH1 to maintain the integrity of the dNTP pool [1].
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| Molecular Formula |
C11H10CL2N4
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| Molecular Weight |
269.13
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| Exact Mass |
268.028
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| Elemental Analysis |
C, 49.09; H, 3.75; Cl, 26.34; N, 20.82
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| CAS # |
1609960-30-6
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| Related CAS # |
TH287 hydrochloride;1638211-05-8
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| PubChem CID |
73441664
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| Appearance |
White to off-white solid powder
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
512.2±60.0 °C at 760 mmHg
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| Flash Point |
263.5±32.9 °C
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| Vapour Pressure |
0.0±1.3 mmHg at 25°C
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| Index of Refraction |
1.681
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| LogP |
3.48
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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 |
2
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| Heavy Atom Count |
17
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| Complexity |
254
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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])C([H])([H])[H])Cl
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| InChi Key |
URWCXPXBBITYLR-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C11H10Cl2N4/c1-15-9-5-8(16-11(14)17-9)6-3-2-4-7(12)10(6)13/h2-5H,1H3,(H3,14,15,16,17)
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| Chemical Name |
6-(2,3-dichlorophenyl)-N4-methylpyrimidine-2,4-diamine
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| Synonyms |
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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 |
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| 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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (9.29 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 (9.29 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 | 3.7157 mL | 18.5784 mL | 37.1568 mL | |
| 5 mM | 0.7431 mL | 3.7157 mL | 7.4314 mL | |
| 10 mM | 0.3716 mL | 1.8578 mL | 3.7157 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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