(R)-GSK-3685032
Based on 1 Customer Validation
(R)-GSK-3685032 is the R-enantiomer of GSK-3685032 (HY-139664) and is a potent, non-covalent, reversible DNMT1-selective inhibitor with an IC50 of 0.036 μM against DNMT1. (R)-GSK-3685032 preferentially binds DNMT1 in a hemimethylated DNA context, inhibits DNA methylation maintenance by occupying the DNMT1 active site loop that inserts into DNA and by interacting with the target recognition domain, thereby inducing DNA hypomethylation and transcriptional activation. (R)-GSK-3685032 is useful for research on DNMT1, acute myeloid leukemia, and B cell humoral immunity.
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研究用途以外に使用した場合、当社は一切の責任を負いかねます。
- 純度 : 98.97%
- CAS 番号: 2170140-50-6
- 分子式: C22H24N6OS
- 分子量:420.53
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保管条件:
4°C, sealed storage, away from moisture and light
* In solvent : -80°C, 6 months; -20°C, 1 month (sealed storage, away from moisture and light)
To place orders, for customer services and technical support, please contact: MedChemExpress USA
Tel: 609-228-6898 E-mail: [email protected] [email protected]
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生物活性
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化学情報
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溶剤 & 溶解度
- プロトコル
- 純度とドキュメンテーション
- 参考文献
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生物活性
製品説明
IC50 & Target
[2]|
DNMT1 0.036 μM (IC50) |
体外実験
(R)-GSK-3685032 (0.1-1 μM; 3 d; LPS (HY-D1056) 25 μg/mL; IL-2 20 ng/mL; IL-5 5 ng/mL) dose-dependently inhibits cell proliferation in primary mouse splenic B cells[1].
(R)-GSK-3685032 (0.1, 0.3, 0.6, 1 μM; 3 d; LPS 25 μg/mL; IL-2 20 ng/mL; IL-5 5 ng/mL) promotes CD98 expression and B220lowCD138high antibody-secreting cell formation in primary mouse splenic B cells, with more pronounced effects above 300 nM, especially in cells that have undergone at least 3 divisions[1].
(R)-GSK-3685032 (30 min) inhibits DNMT1 enzyme activity with an IC50 of 0.036 μM under hemimethylated DNA substrate conditions, whereas its IC50 values for DNMT3A/3L and DNMT3B/3L are both >100 μM[2].
(R)-GSK-3685032 (25 μM; 20 h) does not form a detectable covalent adduct after incubation with recombinant mouse DNMT1 in the presence of hemimethylated DNA, supporting its non-covalent mode of action[2].
(R)-GSK-3685032 (0.13-50000 nM) preferentially stabilizes recombinant DNMT1 in the hemimethylated DNA-bound state; when using unmethylated poly (dIdC) substrate, its potency for inhibiting DNMT1 decreases approximately 15-fold[2].
(R)-GSK-3685032 (400 nM; 24-144 h) induces time-dependent DNA hypomethylation and transcriptional activation in AML cells, with DNA methylation decreasing predominantly during the first 2 days, followed by broader changes in gene expression[2].
(R)-GSK-3685032 (3.2-10000 nM; 2 d) only mildly reduces DNMT1 protein levels in GDM-1 cells, with no immediate significant effects on DNMT3A, DNMT3B, and γH2AX[2].
(R)-GSK-3685032 (6 d) inhibits the proliferation of 51 hematologic tumor cell lines[2].
(R)-GSK-3685032 (3.2-10000 nM; 4 d) dose-dependently decreases global DNA methylation in MV4-11 cells[2].
(R)-GSK-3685032 (0.06-7340 nM; 1-6 d) enhances caspase-3/7 activity in AML cells in a dose- and time-dependent manner, with significant activation observed from day 4[2].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only. Further protocols information, click here.
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Cell Line:Primary murine splenic B cells
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Concentration:0.1, 0.3, 0.6, 1 μM
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Incubation Time:3 d
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Result:Increased CD98 surface expression above 300 nM.
Increased the proportion of B220lowCD138high antibody-secreting cells above 300 nM.
Produced stronger differentiation-associated effects in cells that had undergone at least three divisions.
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Cell Line:AML cell lines
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Concentration:0.06-7340 nM
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Incubation Time:1, 2, 4, 6 d
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Result:Increased caspase-3/7 activity in a dose- and time-dependent manner.
Produced marked caspase activation by day 4.
Parmacokinetics
体内実験
(R)-GSK-3685032 (1-45 mg/kg; s.c.; bid) dose-dependently inhibits tumor growth in MV4-11 and SKM-1 subcutaneous AML xenograft mouse models[2].
(R)-GSK-3685032 (45 mg/kg; s.c.; bid) results in tumor volumes ≤50 mm3 at the last dose in 5 of 10 animals in the MV4-11 subcutaneous xenograft model, and tumor volumes in these 5 animals remain ≤50 mm3 30 days after cessation of dosing[2].
(R)-GSK-3685032 (1-45 mg/kg; s.c.; bid; 30 d) prolongs survival in the disseminated MV4-11 AML mouse model, with clear effects at 15, 30, and 45 mg/kg; overall survival is extended beyond 43 days, and 50% of mice remain alive nearly 7 weeks after drug discontinuation[2].
(R)-GSK-3685032 (1-45 mg/kg; s.c.; bid; ≥4 weeks) is generally well tolerated in mice, with no significant changes in peripheral blood cell parameters at 1 and 5 mg/kg; at higher doses, the reductions in neutrophils and erythrocytes remain less pronounced than those of the control compound and return to normal ranges after a 4-week drug-free observation period[2].
(R)-GSK-3685032 (1-45 mg/kg; s.c.; bid; 8.5 d) dose-dependently decreases global DNA methylation in SKM-1 xenograft tumors, with a maximum reduction of 46% at 45 mg/kg[2].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:C57BL6/J SOPF (6-week-old, male and female, immunized with NP-CGG adsorbed on alum)[1]
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Dosage:30 mg/kg
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Administration:s.c.; twice daily; 7 days (day 7 to day 13 after immunization)
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Result:Caused a 5-fold reduction in the percentage of splenic GC B cells relative to vehicle.
Induced significant hypomethylation of LINE-1 repeats in residual cells (18.2% of unmethylated CpG vs. 7.9% for vehicle).
Increased the percentage of CCR6+ CD38+ pre-MBCs among CD95+ GL7+ GC B cells fourfold.
Increased surface expression of CD98 in CCR6- CD38- CD95+ GL7+ GC B cells 1.4-fold.
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Animal Model:CD1-Foxn1
(female, 12 weeks of age, subcutaneous MV4-11 xenograft model)[2] -
Dosage:1, 5, 15, 30, and 45 mg/kg
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Administration:s.c.; twice daily (BID); 35 days
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Result:Dose-dependently inhibited tumor growth.
Produced clear tumor regression at ≥30 mg/kg.
At 45 mg/kg, reduced tumors to ≤50 mm3 in 5/10 animals by day 35.
The same five animals maintained tumor volumes ≤50 mm3 after 30 days without dosing.
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Animal Model:NOD.CB17-Prkdc
1NCrCrl (8-11 weeks of age, subcutaneous SKM-1 xenograft model)[2] -
Dosage:1, 5, 15, 30, and 45 mg/kg
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Administration:s.c.; twice daily (BID); 20 days
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Result:Dose-dependently inhibited tumor growth.
Produced clear tumor regression at ≥30 mg/kg.
Reduced global tumor DNA methylation at all examined doses.
Produced a maximal 46% loss of global DNA methylation at 45 mg/kg after 8.5 days.
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Animal Model:NOD.CB17-Prkdcscid/NCrCrl (female, 10 weeks old, systemic/disseminated AML model)[2]
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Dosage:15, 30, and 45 mg/kg
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Administration:s.c.; twice daily (BID); 30 days
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Result:Prolonged survival at 15, 30, and 45 mg/kg.
Extended survival by >43 days overall.
Maintained survival of 50% of mice nearly 7 weeks after dosing ended.
化学情報
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CAS 番号 2170140-50-6
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性状 Solid
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分子量 420.53
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分子式 C22H24N6OS
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Color White to off-white
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SMILES
N#CC1=C(N2CCC(CC2)N)N=C(C(C#N)=C1CC)S[C@H](C3=CC=CC=C3)C(N)=O
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輸送条件
Room temperature in continental US; may vary elsewhere.
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保管条件
4°C, sealed storage, away from moisture and light
* In solvent : -80°C, 6 months; -20°C, 1 month (sealed storage, away from moisture and light)
溶剤 & 溶解度
体外:
DMSO : 60 mg/mL (142.68 mM; Need ultrasonic; Hygroscopic DMSO has a significant impact on the solubility of product, please use newly opened DMSO)
Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month (sealed storage, away from moisture and light). When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.
Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month (sealed storage, away from moisture and light). When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.
濃度 (開始) × 体積 (開始) = 濃度 (終了) × 体積 (終了)
プロトコル
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Cell Cytotoxicity Assay
Cytotoxicity assays are usually based on the assessment of cell membrane damage, which can also be indirectly detected by measuring cell viability. Detection methods include MTT assay, CKK-8 assay, LDH assay and ATP assay, etc.
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Research Protocol for Epigenomic Data Analysis
Epigenomic data analysis identifies genome-wide regulatory features that influence gene expression, chromatin state, and phenotype without changing the underlying DNA sequence. In this strategy, the core regulatory layer includes chromatin accessibility, transcription-factor or histone-mark occupancy, DNA methylation, and chromatin-state patterns; these features are measured by sequencing-based assays and interpreted as regulatory elements, promoters, enhancers, repressive domains, methylated cytosines, or candidate phenotype-associated chromatin programs. The literature links epigenomic features to phenotype by showing that functional genomic elements can be mapped across human cell types and tissues, and that integrated epigenomic maps reveal cell-type-specific regulatory programs. ENCODE integrated transcription, chromatin accessibility, transcription-factor occupancy, and histone modification data to annotate functional elements in the human genome, while the Roadmap Epigenomics Co
純度とドキュメンテーション
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データシート (300 KB)
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取扱説明書 (2659 KB)
参考文献
[1]. Cousu C, et al. Germinal center output is sustained by HELLS-dependent DNA-methylation-maintenance in B cells. Nature communications. 2023 Sep 14;14(1):5695. [Content Brief]
[2]. Pappalardi MB, et al. Discovery of a first-in-class reversible DNMT1-selective inhibitor with improved tolerability and efficacy in acute myeloid leukemia. Nature cancer. 2021 Oct;2(10):1002-1017. [Content Brief]
Complete Stock Solution Preparation Table
Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month (sealed storage, away from moisture and light). When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.
| Optional Solvent | Concentration Solvent Mass | 1 mg | 5 mg | 10 mg | 25 mg |
|---|---|---|---|---|---|
| DMSO | 1 mM | 2.3780 mL | 11.8898 mL | 23.7795 mL | 59.4488 mL |
| 5 mM | 0.4756 mL | 2.3780 mL | 4.7559 mL | 11.8898 mL | |
| 10 mM | 0.2378 mL | 1.1890 mL | 2.3780 mL | 5.9449 mL | |
| 15 mM | 0.1585 mL | 0.7927 mL | 1.5853 mL | 3.9633 mL | |
| 20 mM | 0.1189 mL | 0.5945 mL | 1.1890 mL | 2.9724 mL | |
| 25 mM | 0.0951 mL | 0.4756 mL | 0.9512 mL | 2.3780 mL | |
| 30 mM | 0.0793 mL | 0.3963 mL | 0.7927 mL | 1.9816 mL | |
| 40 mM | 0.0594 mL | 0.2972 mL | 0.5945 mL | 1.4862 mL | |
| 50 mM | 0.0476 mL | 0.2378 mL | 0.4756 mL | 1.1890 mL | |
| 60 mM | 0.0396 mL | 0.1982 mL | 0.3963 mL | 0.9908 mL | |
| 80 mM | 0.0297 mL | 0.1486 mL | 0.2972 mL | 0.7431 mL | |
| 100 mM | 0.0238 mL | 0.1189 mL | 0.2378 mL | 0.5945 mL |
(R)-GSK-3685032 関連分類
HY-139664A 関連分類
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