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| Targets |
TH-10785 specifically targets 8-oxoguanine DNA glycosylase 1 (OGG1), the key enzyme in the base excision repair (BER) pathway responsible for removing oxidized guanine bases (8-oxoG) from DNA. TH-10785 interacts with specific amino acids in the active site of OGG1, including phenylalanine-319 and glycine-42. By binding to these residues, the compound increases the enzymatic activity of OGG1, particularly its beta- and delta-lyase activities, which are involved in cleaving the DNA backbone after lesion excision.
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| ln Vitro |
AP sites can become new substrates when TH10785 (6.25 μM, 30 min) induces de novo β,δ-elimination in vitro [1]. By targeting AP sites, TH10785 (10 μM, 0–2 minutes) enables OGG1 to improve DNA repair [1]. TH10785 (0–20 μM, 72 hours) causes cells to become dependent on PNKP1 and activates OGG1 β and δ-lyase [1]. When an AP site analog containing double-stranded DNA (KD=1.3 μM) is added, the affinity of TH10785 (2 μM) for OGG1 (KD=5.5 μM) increases [1].
In vitro, TH-10785 activates OGG1-mediated DNA repair. The compound enhances OGG1's ability to recognize and excise 8-oxoG lesions from DNA. It increases the rate of the enzymatic reaction by promoting the beta- and delta-lyase activities of OGG1. In cell-free assays using purified OGG1 and a DNA substrate containing a single 8-oxoG lesion, treatment with TH-10785 (0-20 uM) results in a concentration-dependent increase in the cleavage of the damaged DNA strand. This enhanced activity leads to more efficient repair of oxidative DNA damage. |
| ln Vivo |
In vivo, TH-10785 has been shown to improve DNA repair in cellular models. By activating OGG1, the compound enhances the removal of 8-oxoG lesions from the genome, reducing the accumulation of oxidative DNA damage that can lead to mutations and cellular dysfunction. In cells exposed to oxidative stress, treatment with TH-10785 improves the recruitment of OGG1 to sites of DNA damage. The compound may also influence cellular sensitivity to DNA-damaging agents, such as chemotherapeutic drugs or radiation, by modulating the base excision repair pathway. Detailed in vivo efficacy data is limited.
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| Enzyme Assay |
For non-cell-based enzyme activity assays, a standard protocol uses purified recombinant human OGG1 and a fluorescently labeled DNA duplex containing a single 8-oxoG lesion. TH-10785 is pre-incubated with OGG1 (10 nM) in reaction buffer (20 mM HEPES, pH 7.5, 50 mM KCl, 1 mM EDTA, 0.1 mg/mL BSA) for 15 minutes at 37degC. The reaction is initiated by adding the DNA substrate (100 nM). After 30 minutes, the reaction is stopped by adding formamide loading buffer. The cleavage products are separated by denaturing PAGE and quantified by fluorescence imaging. The fold activation (EC50) is calculated from the dose-response curve.
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| Cell Assay |
Cell Viability Assay[1]
Cell Types: U2OS Cell Tested Concentrations: 0-20 μM Incubation Duration: 72 hrs (hours) Experimental Results: Reduction by combination of TH10785 and PNKP1 inhibition. Western Blot Analysis[1] Cell Types: U2OS Cell Tested Concentrations: 0.65 μM; 10 μM Incubation Duration: 30 minutes; 24 hrs (hours) Experimental Results: In the presence of TH10785, combined PNKP1 inhibition and OGG1 inhibition of AP sites via β, δ-elimination APE1-independent de novo β, δ-elimination causes upregulation of DDR members. RT-PCR[1] Cell Types: U2OS Cell Tested Concentrations: 10 μM Incubation Duration: 1 hour Experimental Results: diminished oxidative damage in guanine-rich regions of the genome. Immunofluorescence[1] Cell Types: U2OS OGG1-GFP Cell Tested Concentrations: 1 μM Incubation Duration: 0-2 minutes Experimental Results: More OGG1 is recruited at the laser injury site. For in vitro cell-based assays, human cell lines (e.g., HeLa or U2OS) are seeded in 6-well plates and cultured to 70-80% confluency. Cells are treated with TH-10785 (0-20 uM) for 24-72 hours. Oxidative DNA damage can be induced by treating cells with hydrogen peroxide (50-200 uM) or potassium bromate (1 mM) for 30 minutes before compound treatment. After treatment, genomic DNA is extracted, and the levels of 8-oxoG are quantified by HPLC-ECD or by an ELISA-based 8-oxoG detection kit. Alternatively, recruitment of OGG1 to sites of oxidative DNA damage can be visualized by immunofluorescence using an anti-OGG1 antibody. |
| Animal Protocol |
For in vivo animal studies, a mouse model of oxidative stress-induced DNA damage can be used. Mice are treated with TH-10785 via intraperitoneal injection (e.g., 10-50 mg/kg) daily for 5-14 days. Control mice receive vehicle. At study endpoint, tissues (liver, kidney, brain) are harvested, and genomic DNA is extracted. 8-oxoG levels in the DNA are quantified by HPLC-ECD or by mass spectrometry. Additionally, markers of DNA repair (e.g., OGG1 activity assay from tissue lysates) can be measured. The compound's ability to protect against oxidative damage-induced tissue injury can be assessed by histology and by measuring serum markers of liver or kidney injury.
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| ADME/Pharmacokinetics |
Specific pharmacokinetic data for TH-10785 is not publicly available. The compound has a molecular weight of 267.37 g/mol and a molecular formula of C17H21N3. It is a small, lipophilic molecule (cLogP approximately 3-4), suggesting good cell membrane permeability. For in vivo use, the compound can be formulated in DMSO or PEG400 for intraperitoneal administration. The compound's in vitro activity at 0-20 uM suggests that these concentrations may be achievable in vivo with appropriate dosing. Detailed ADME (absorption, distribution, metabolism, excretion) studies would be required for preclinical development.
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| Toxicity/Toxicokinetics |
Specific toxicology data for TH-10785 is not publicly available, as it is a research compound not intended for human use. In cell culture studies, TH-10785 is typically used at concentrations up to 20 uM without significant cytotoxicity. No acute toxicity data from animal studies is available in the public domain. Standard safety precautions (gloves, lab coat) should be used when handling the compound powder. It should be stored at -20degC for long-term stability. The compound is not classified as a carcinogen or reproductive hazard based on available information.
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| References | |
| Additional Infomation |
TH-10785 is a first-in-class OGG1 activator and represents a novel approach to enhancing DNA repair capacity. OGG1 is a critical enzyme in the base excision repair pathway, and its dysfunction is associated with aging, neurodegenerative diseases, and cancer susceptibility. By activating OGG1, TH-10785 may have therapeutic potential for conditions characterized by elevated oxidative DNA damage, such as neurodegeneration, ischemia-reperfusion injury, and chronic inflammation. The compound is also a valuable chemical probe for studying the role of OGG1 in cellular responses to oxidative stress. It is not approved for clinical use.
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| Molecular Formula |
C17H21N3
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| Molecular Weight |
267.37
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| Exact Mass |
267.173
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| CAS # |
1002801-51-5
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| PubChem CID |
8078523
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| Appearance |
White to off-white solid powder
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| LogP |
4.2
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
20
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| Complexity |
322
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| Defined Atom Stereocenter Count |
0
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| SMILES |
N1=C2C(C=CC=C2)=C(NC2CCCCC2)N=C1C1CC1
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| InChi Key |
ZQMGQZOHIDOPCQ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C17H21N3/c1-2-6-13(7-3-1)18-17-14-8-4-5-9-15(14)19-16(20-17)12-10-11-12/h4-5,8-9,12-13H,1-3,6-7,10-11H2,(H,18,19,20)
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| Chemical Name |
N-cyclohexyl-2-cyclopropylquinazolin-4-amine
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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 : ≥ 100 mg/mL (~374.01 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (9.35 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), suspension 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 (9.35 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 (9.35 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 | 3.7401 mL | 18.7007 mL | 37.4014 mL | |
| 5 mM | 0.7480 mL | 3.7401 mL | 7.4803 mL | |
| 10 mM | 0.3740 mL | 1.8701 mL | 3.7401 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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