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| Targets |
TH-5427 targets NUDT5 (Nudix hydrolase 5), an enzyme that hydrolyzes ADP-ribose and related metabolites. NUDT5 plays a critical role in nuclear ATP synthesis from poly(ADP-ribose) (PAR) breakdown products, which is required for chromatin remodeling and gene regulation in response to hormonal stimuli. By inhibiting NUDT5 with high potency (IC50 = 29 nM), TH-5427 blocks the production of nuclear ATP from PAR, thereby disrupting energy-dependent chromatin remodeling and gene expression programs.
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| ln Vitro |
In vitro, TH-5427 is a lead NUDT5 inhibitor with an IC50 of 29 nM in biochemical assays. In HL-60 cell lysates, TH-5427 at 20 μM stabilizes NUDT5 to nearly the same levels as observed in the 37°C DMSO control. The compound blocks progestin-dependent, PAR-derived nuclear ATP synthesis and subsequent chromatin remodeling, gene regulation, and proliferation in breast cancer cells. Its potent and selective NUDT5 inhibition makes it valuable for studying ADP-ribose metabolism and breast cancer biology.
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| ln Vivo |
In vivo, TH-5427 has potential for breast cancer research based on its ability to block progestin-dependent nuclear ATP synthesis and proliferation in breast cancer cells. However, specific in vivo efficacy data for TH-5427 have not been detailed in the available literature. The compound's ability to inhibit NUDT5-mediated nuclear ATP production suggests it may have applications in studying hormone-dependent cancers and metabolic regulation. Further preclinical studies would be required for full characterization.
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| Enzyme Assay |
For in vitro enzyme assays, recombinant NUDT5 protein is incubated with a substrate such as ADP-ribose or related metabolites in assay buffer. The test compound is added at various concentrations (0.1-1000 nM). Enzyme activity is measured by monitoring the production of reaction products using spectrophotometric or fluorometric methods, or by using coupled assays. IC50 values are calculated by fitting dose-response curves. TH-5427 shows an IC50 of 29 nM in these assays.
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| Cell Assay |
For cell-based assays, breast cancer cell lines such as MCF-7 or other hormone-responsive cells are treated with TH-5427 at concentrations ranging from 0.1-50 µM. Nuclear ATP levels are measured using bioluminescent assays. Chromatin remodeling and gene expression are assessed by analyzing histone modifications and target gene expression by Western blotting or qRT-PCR. Cell proliferation is measured using MTT or CellTiter-Glo assays to assess the functional consequences of NUDT5 inhibition.
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| Animal Protocol |
For in vivo efficacy studies, immunodeficient mice would be implanted with breast cancer xenografts. When tumors reach a predetermined size, mice would be randomized and treated with TH-5427 via appropriate routes at doses determined from pharmacokinetic studies. Tumor volumes would be measured twice weekly. At study endpoint, tumors would be collected for analysis of NUDT5 activity, nuclear ATP levels, and proliferation markers. However, specific in vivo protocols for TH-5427 have not been detailed in the available literature.
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| ADME/Pharmacokinetics |
Pharmacokinetic properties of TH-5427 have not been fully characterized in the available literature. The compound is soluble in DMSO. Storage is recommended at -20°C for long-term stability. Further detailed PK parameters including half-life, oral bioavailability, and tissue distribution would be required for in vivo studies. The compound is for research use only and is not intended for human or veterinary use.
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| Toxicity/Toxicokinetics |
Toxicological data for TH-5427 have not been extensively reported in the available literature. As a research compound, it is intended for laboratory use only and is not for human or veterinary use. Standard safety precautions should be followed when handling this compound. Comprehensive toxicology studies would be required before any clinical development.
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| References | |
| Additional Infomation |
NUDT5 inhibitor blocks hormone signaling in breast cancer cells; structure published for the first time.
TH-5427 is a potent and selective NUDT5 inhibitor with an IC50 of 29 nM. It blocks progestin-dependent, PAR-derived nuclear ATP synthesis and subsequent chromatin remodeling, gene regulation, and proliferation in breast cancer cells. TH-5427 is used in research to study NUDT5 activity, ADP-ribose metabolism, and breast cancer biology. It is a research tool and is not approved for clinical use. |
| Molecular Formula |
C20H20CL2N8O3
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|---|---|
| Molecular Weight |
491.33
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| Exact Mass |
490.103
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| CAS # |
2253744-56-6
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| Related CAS # |
TH5427 hydrochloride;2253744-57-7
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| PubChem CID |
132472992
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| Appearance |
White to off-white solid powder
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| LogP |
1.7
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
33
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| Complexity |
759
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CN1C2=C(C(=O)N(C1=O)C)N(C(=N2)N3CCNCC3)CC4=NN=C(O4)C5=CC(=C(C=C5)Cl)Cl
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| InChi Key |
QXCXMVYVUHVFLP-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C20H20Cl2N8O3/c1-27-16-15(18(31)28(2)20(27)32)30(19(24-16)29-7-5-23-6-8-29)10-14-25-26-17(33-14)11-3-4-12(21)13(22)9-11/h3-4,9,23H,5-8,10H2,1-2H3
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| Chemical Name |
7-[[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl]-1,3-dimethyl-8-piperazin-1-ylpurine-2,6-dione
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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 Note: This product requires protection from light (avoid light exposure) during transportation and storage. |
| 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 : ~5 mg/mL (~10.18 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 0.5 mg/mL (1.02 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 5.0 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: ≥ 0.5 mg/mL (1.02 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 5.0 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0353 mL | 10.1765 mL | 20.3529 mL | |
| 5 mM | 0.4071 mL | 2.0353 mL | 4.0706 mL | |
| 10 mM | 0.2035 mL | 1.0176 mL | 2.0353 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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