GSK-3685032 是一种非时间依赖、非共价、可逆的DNMT1选择性抑制剂，IC50=0.036 μM。GSK-3685032 诱导 DNA 甲基化丧失、转录激活和癌细胞生长抑制。
| 生物活性 | GSK-3685032 is a non-time-dependent, noncovalently, first-in-class reversibleDNMT1-selective inhibitor, with anIC50of 0.036 μM. GSK-3685032 induces robust loss of DNA methylation, transcriptional activation, andcancercell growth inhibition[1]. |
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体外研究
(In Vitro) | GSK-3685032 (6 days) has cell growth inhibition of majority cancer cell lines, with a median growth IC50value of 0.64 μM[1].
GSK-3685032 (0.1-1000 nM, 1-6 days) exhibits growth inhibition after 3 days, with decreasing growth IC50throughout a 6 d time course[1].
GSK3685032 (10-10000 nM, day 4) dose-dependently increases the immune-related gene transcription[1].
GSK3685032 (3.2-10,000 nM, 2 days) inhibits DNMT1 protein expression[1].
GSK3685032 induces DNA hypomethylation and gene activation[1].
Cell Proliferation Assay[1] | Cell Line: | 15 leukemia, 29 lymphoma and 7 multiple myeloma cell lines, e.g., EOL-1, Ki-JK, MM.IR cells. | | Concentration: | 0.01-100 μM | | Incubation Time: | 6 days | | Result: | Showed cell growth inhibition of majority cancer cell lines, with a median growth IC50value of 0.64 μM. |
Cell Proliferation Assay[1] | Cell Line: | MV4-11 cells | | Concentration: | 0.1-1000 nM | | Incubation Time: | 1-6 days | | Result: | Exhibited growth inhibition after 3 days, with decreasing growth IC50throughout a 6 d time course. |
RT-PCR[1] | Cell Line: | MV4-11 cells | | Concentration: | 10-10000 nM | | Incubation Time: | 4 days | | Result: | Dose-dependent increased of CXCL11, IFI27, HLA-DQA1 and MAGEA4 following treatment of MV4-11 cells. |
Western Blot Analysis[1] | Cell Line: | GDM-1 cells | | Concentration: | 3.2-10,000 nM | | Incubation Time: | 2 days | | Result: | Inhibited DNMT1 protein expression |
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体内研究
(In Vivo) | GSK-3685032 (1-45 mg/kg; subcutaneous twice daily for 28 days) inhibits tumor growth in the subcutaneous MV4-11 or SKM-1 xenograft models[1].
Summary of mouse pharmacokinetic parameters for GSK-3685032[1]
| Dose,Route | Cmax
(ng/mL) | AUC0-8hr
(h*ng/mL) | DNAUC
(h*kg*ng/mL/mg) | Clearance
(mL/min/kg) | Volumedss
(L/kg) | T1/2
(h) | | 2 mg/kg,IV | 5103 | 2418 | 1209 | 13 | 1.3 | 1.8 | | 2 mg/kg,SC | 252 | 921 | 461 | NA | NA | 2.8 | | 2 mg/kg,SC | 5473 | 15400 | 513 | NA | NA | ND |
| Animal Model: | MV4-11 xenograft models (female CD1-Foxn1mice, 12 weeks of age) or SKM-1 xenograft models (NOD. CB17-Prkdc1NCrCrl mice, 8-11 weeks of age)[1] | | Dosage: | 1, 5, 15, 30, 45 mg/kg (10% captisol adjusted to pH 4.5-5 with 1 M acetic acid, stored for up to 1 week at 4 ℃) | | Administration: | Subcutaneous injection, twice daily for 4 weeks | | Result: | Revealed statistically significant dose-dependent tumor growth inhibition with clear regression at ≥30 mg/kg. |
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| 运输条件 | Room temperature in continental US; may vary elsewhere. |
| 储存方式 | | Powder | -20°C | 3 years | | 4°C | 2 years | | In solvent | -80°C | 6 months | | -20°C | 1 month |
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| 溶解性数据 | In Vitro: DMSO : 25 mg/mL(59.45 mM;Need ultrasonic) 配制储备液 | 1 mM | 2.3780 mL | 11.8898 mL | 23.7795 mL | | 5 mM | 0.4756 mL | 2.3780 mL | 4.7559 mL | | 10 mM | 0.2378 mL | 1.1890 mL | 2.3780 mL |
*请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。
储备液的保存方式和期限：-80℃, 6 months; -20℃, 1 month。-80℃ 储存时，请在 6 个月内使用，-20℃ 储存时，请在 1 个月内使用。 In Vivo: 请根据您的实验动物和给药方式选择适当的溶解方案。以下溶解方案都请先按照In Vitro方式配制澄清的储备液，再依次添加助溶剂： ——为保证实验结果的可靠性，澄清的储备液可以根据储存条件，适当保存；体内实验的工作液，建议您现用现配，当天使用；
以下溶剂前显示的百
分比是指该溶剂在您配制终溶液中的体积占比；如在配制过程中出现沉淀、析出现象，可以通过加热和/或超声的方式助溶 1. 请依序添加每种溶剂： 10% DMSO 40%PEG300 5%Tween-80 45% saline Solubility: ≥ 2.5 mg/mL (5.94 mM); Clear solution
此方案可获得 ≥ 2.5 mg/mL (5.94 mM，饱和度未知) 的澄清溶液。 以 1 mL 工作液为例，取 100 μL 25.0 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀；向上述体系中加入50 μL Tween-80，混合均匀；然后继续加入 450 μL生理盐水定容至 1 mL。 2. 请依序添加每种溶剂： 10% DMSO 90% (20%SBE-β-CDin saline) Solubility: ≥ 2.5 mg/mL (5.94 mM); Clear solution
此方案可获得 ≥ 2.5 mg/mL (5.94 mM，饱和度未知) 的澄清溶液。 以 1 mL 工作液为例，取 100 μL 25.0 mg/mL 的澄清 DMSO 储备液加到 900 μL20% 的 SBE-β-CD 生理盐水水溶液中，混合均匀。 3. 请依序添加每种溶剂： 10% DMSO 90%corn oil Solubility: ≥ 2.5 mg/mL (5.94 mM); Clear solution
此方案可获得 ≥ 2.5 mg/mL (5.94 mM，饱和度未知) 的澄清溶液，此方案不适用于实验周期在半个月以上的实验。 以 1 mL 工作液为例，取 100 μL 25.0 mg/mL 的澄清 DMSO 储备液加到 900 μL玉米油中，混合均匀。 *以上所有助溶剂都可在本网站选购。
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