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| 1mg |
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| 5mg |
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| 10mg |
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| Other Sizes |
| Targets |
GSK3735967 targets DNA methyltransferase 1 (DNMT1) with high potency (IC50 = 40 nM). DNMT1 is responsible for maintaining DNA methylation patterns during replication, and its dysregulation is associated with various cancers. As a non-nucleoside inhibitor, GSK3735967 does not mimic the natural cytosine substrate but instead binds to DNMT1 through a unique mechanism involving its planar dicyanopyridine core that intercalates into hemimethylated CpG sites. The compound also interacts with histone H4K20me3 through one of its three binding sites.
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| ln Vitro |
In a dose-dependent manner, GSK3735967 (0.1–1000 nM) suppresses DNMT1 activity [1].
In vitro, GSK3735967 demonstrates potent DNMT1 inhibitory activity at nanomolar concentrations (IC50 = 40 nM). Its planar dicyanopyridine core specifically embeds into DNMT1-bound hemimethylated CpG dinucleotides. The compound's mechanism involves three distinct binding sites, including interaction with histone H4K20me3. By inhibiting DNMT1, GSK3735967 reduces DNA methylation, leading to the re-expression of silenced tumor suppressor genes and induction of cell cycle arrest in cancer cells. |
| ln Vivo |
In vivo data for GSK3735967 is limited in publicly available sources. As a DNMT1 inhibitor with potent in vitro activity, the compound is expected to demonstrate antitumor efficacy in preclinical cancer models. DNMT1 inhibitors have shown activity in hematological malignancies and solid tumors by reversing aberrant DNA methylation patterns. However, specific published in vivo efficacy studies for GSK3735967 are not widely reported. The compound is primarily used as a research tool for studying DNA methylation and epigenetic regulation in oncology.
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| Enzyme Assay |
The in vitro DNMT1 inhibition assay for GSK3735967 typically uses recombinant DNMT1 enzyme and a hemimethylated DNA substrate. The assay measures the transfer of methyl groups from S-adenosylmethionine (SAM) to the DNA substrate, with inhibition detected by radioactive or fluorescence-based methods. IC50 values are calculated from dose-response curves. The compound's binding to DNMT1 can be further characterized by surface plasmon resonance or isothermal titration calorimetry to confirm its non-nucleoside, reversible binding mechanism.
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| Cell Assay |
Cellular activity of GSK3735967 is assessed in cancer cell lines where DNMT1 is overexpressed or aberrantly active. Cells are treated with varying concentrations of the compound for 72-96 hours, and DNA methylation levels are measured using bisulfite sequencing or methylation-specific PCR. Cell viability and proliferation are assessed using standard assays such as MTT or CellTiter-Glo. Apoptosis and cell cycle arrest are evaluated by flow cytometry. Re-expression of silenced tumor suppressor genes is confirmed by qPCR or Western blotting.
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| Animal Protocol |
In vivo studies for GSK3735967 would typically involve xenograft mouse models of hematological or solid tumors. The compound would be administered orally or intravenously at doses determined by pharmacokinetic studies. Tumor growth inhibition would be measured over several weeks, and pharmacodynamic markers such as global DNA methylation levels and re-expression of silenced genes would be assessed in tumor tissues. However, specific published in vivo protocols for GSK3735967 are not available in the current literature.
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| ADME/Pharmacokinetics |
Pharmacokinetic data for GSK3735967 is not extensively reported in publicly available sources. The compound has a molecular weight of 477.62 g/mol and is soluble in DMSO at 25 mg/mL (52.34 mM). As a small molecule DNMT1 inhibitor, it is expected to have moderate oral bioavailability. Detailed PK parameters such as half-life, clearance, and volume of distribution are not available in the current literature for this research compound.
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| Toxicity/Toxicokinetics |
Toxicity data for GSK3735967 is limited in publicly available sources. As with all research compounds, GSK3735967 is intended for research use only and not for human therapeutic applications. Standard in vitro cytotoxicity assays in normal cell lines and in vivo tolerability studies in animal models would be required for a complete toxicity assessment. No specific toxicity data has been reported for this compound in the available literature.
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| References |
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| Additional Infomation |
GSK3735967 is a selective, reversible, non-nucleoside DNMT1 inhibitor with a unique planar dicyanopyridine core that embeds into hemimethylated CpG dinucleotides. It has three binding sites, including interaction with histone H4K20me3. By inhibiting DNMT1, the compound blocks symmetric arginine dimethylation and induces tumor cell cycle arrest. It is used in research on hematological malignancies and solid tumors. The compound serves as a valuable tool for studying DNA methylation, epigenetic regulation, and cancer biology.
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| Molecular Formula |
C25H31N7OS
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|---|---|
| Molecular Weight |
477.62494301796
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| Exact Mass |
477.231
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| CAS # |
2170136-86-2
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| PubChem CID |
132233120
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| Appearance |
Off-white to yellow solid powder
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| LogP |
2.3
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
34
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| Complexity |
753
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C(NCC1=CC=C(CSC2=NC(N3CCCN(C)CC3)=C(C#N)C(CC)=C2C#N)C=C1)(=O)CN
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| InChi Key |
QPLFMVVUDGWTPG-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C25H31N7OS/c1-3-20-21(13-26)24(32-10-4-9-31(2)11-12-32)30-25(22(20)14-27)34-17-19-7-5-18(6-8-19)16-29-23(33)15-28/h5-8H,3-4,9-12,15-17,28H2,1-2H3,(H,29,33)
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| Chemical Name |
2-amino-N-[[4-[[3,5-dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl]sulfanylmethyl]phenyl]methyl]acetamide
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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 : 31.25 mg/mL (65.43 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.35 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), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 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: 2.08 mg/mL (4.35 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 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: ≥ 2.08 mg/mL (4.35 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 | 2.0937 mL | 10.4686 mL | 20.9371 mL | |
| 5 mM | 0.4187 mL | 2.0937 mL | 4.1874 mL | |
| 10 mM | 0.2094 mL | 1.0469 mL | 2.0937 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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