Guadecitabine sodium
(Synonyms: SGI-110 sodium; S-110 sodium) 目录号 : GC36196
Guadecitabine sodium (SGI-110 sodium) 是第二代 DNA 甲基转移酶 (DNMT) 抑制剂，用于研究急性髓性白血病 (AML) 和骨髓增生异常综合征 (MDS)。
Cas No.:929904-85-8
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| Cell experiment [1]: | |
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Cell lines |
Leukemic cell lines(HL60, KG1a, U937) |
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Preparation Method |
To evaluate the effect of Guadecitabine treatment on Cancer Testis Antigen methylation, HL60, U937, and KG1a leukemic cell lines were treated with Guadecitabine and harvested on day 5. |
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Reaction Conditions |
Leukemic cell line were treated with Guadecitabine ( 0.1, 1.0 and 5μM) for 5 days. |
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Applications |
Guadecitabine treatment resulted in significant reductions of LINE-1 and NY-ESO-1 promoter methylation in HL60, U937 and KG1a cells, as determined by quantitative bisulfite pyrosequencing.MAGE-A3/6 was also hypomethylated following Guadecitabine treatment in all cell lines. |
| Animal experiment [2]: | |
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Animal models |
SCID mice |
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Preparation Method |
OVCAR3 cells were implanted into the hindquarters of SCID mice. After 2–3 weeks, when macroscopic tumors were formed, mice were treated with Guadecitabine for 5day. |
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Dosage form |
3 mg/kg/day, subcutaneous treatment |
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Applications |
OVCAR3 tumors were treated with 3 mg/kg/d, 5 days Guadecitabine or vehicle control subcutaneously, 3 days later, injected with NY-ESO-1-specific CD8+ T-cells or vehicle control (PBS) intra-tumorally. The combination of Guadecitabine and NY-ESO-1 specific T-cells showed delayed tumor growth in comparison with mice treated with Guadecitabine or NY-ESO-1-specific CD8 +T-cells alone.these data suggest Guadecitabine treatment enhances NY-ESO-1-specific antitumor responses in vivo. |
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References: [1]. Srivastava P, Paluch BE,et al. Immunomodulatory action of SGI-110, a hypomethylating agent, in acute myeloid leukemia cells and xenografts. Leuk Res. 2014 Nov;38(11):1332-41. [2]. Srivastava P, Paluch BE,et al. Immunomodulatory action of the DNA methyltransferase inhibitor SGI-110 in epithelial ovarian cancer cells and xenografts. Epigenetics. 2015;10(3):237-46. |
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Guadecitabine is a novel hypomethylating dinucleotide of decitabine and deoxyguanosine that is resistant to degradation by cytidine deaminase. Guadecitabine Sodium is the easily dissolved form of Guadecitabine[1].
Guadecitabine (0.1, 0.3, 1, 5μM, 48h) increased sensitivity to cisplatin for both the parental and the resistant A2780 cells. Although among other ovarian cancer cell lines, the parental A2780- cisplatin resistant cells is considered to be cisplatin “sensitive”, it has a relatively high IC50 for the drug[2].
Guadecitabine (50nM-2μM, 24h) pretreatment synergistically interacted with ASTX660 to induce cell death in five AML cell lines (MOLM-13, ML-2, MV4-11, PLB-985, KG-1) with various genetic backgrounds and representing different AML subtypes?[3].
Tumor-bearing immune-deficient mice were exposed subcutaneously to Guadecitabine at doses of 3, 6.1, or 10 mg/kg, daily for 5 days, with tumors harvested on day 7. Most mice treated on the 5 day schedule with 10mg/kg/day Guadecitabine died; all mice treated with 6.1mg/kg/day Guadecitabine developed gastrointestinal toxicity. Minimal toxicity was observed in mice treated with 3mg/kg/day. Guadecitabine treatment caused hypomethylation of?LINE-1?and?NY-ESO-1?at all doses[4].
References:
[1].Issa JJ, Roboz G, et al. Safety and tolerability of guadecitabine (SGI-110) in patients with myelodysplastic syndrome and acute myeloid leukaemia: a multicentre, randomised, dose-escalation phase 1 study. Lancet Oncol. 2015 Sep;16(9):1099-1110.
[2].Fang F, Munck J, et al. The novel, small-molecule DNA methylation inhibitor SGI-110 as an ovarian cancer chemosensitizer. Clin Cancer Res. 2014 Dec 15;20(24):6504-16.
[3].Dittmann J, Haydn T, et al. Next-generation hypomethylating agent SGI-110 primes acute myeloid leukemia cells to IAP antagonist by activating extrinsic and intrinsic apoptosis pathways. Cell Death Differ. 2020 Jun;27(6):1878-1895.
[4].rivastava P, Paluch BE, et al. Immunomodulatory action of SGI-110, a hypomethylating agent, in acute myeloid leukemia cells and xenografts. Leuk Res. 2014 Nov;38(11):1332-41.
Guadecitabine 是地西他滨和脱氧鸟苷的新型低甲基化二核苷酸，可抵抗胞苷脱氨酶的降解。 Guadecitabine Sodium 是 Guadecitabine 的易溶解形式[1]。
Guadecitabine (0.1, 0.3, 1, 5μM, 48h) 增加了亲本细胞和耐药 A2780 细胞对顺铂的敏感性。尽管在其他卵巢癌细胞系中，亲本 A2780-顺铂耐药细胞被认为对顺铂"敏感"，但其对该药物具有相对较高的 IC50[2]。
Guadecitabine (50nM-2μM, 24h) 预处理与 ASTX660 协同作用，在具有不同遗传背景的五种 AML 细胞系（MOLM-13、ML-2、MV4-11、PLB-985、KG-1）中诱导细胞死亡并代表不同的 AML 子类型[3]。
携带肿瘤的免疫缺陷小鼠皮下暴露于剂量为 3、6.1 或 10 mg/kg 的瓜地西他滨，持续 5 天，并在第 7 天收获肿瘤。大多数小鼠在 5 天的治疗方案中接受 10mg /kg/day 瓜地西他滨死亡；所有用 6.1mg/kg/天 Guadecitabine 治疗的小鼠都出现了胃肠道毒性。在用 3mg/kg/天处理的小鼠中观察到最小毒性。瓜地西他滨治疗导致所有剂量的 LINE-1 和 NY-ESO-1 低甲基化[4]。
| Cas No. | 929904-85-8 | SDF | |
| 别名 | SGI-110 sodium; S-110 sodium | ||
| Canonical SMILES | O=C1C2=C(N([C@H]3C[C@H](O)[C@@H](COP(O[C@@H]4[C@@H](CO)O[C@@H](N5C=NC(N)=NC5=O)C4)([O-])=O)O3)C=N2)NC(N)=N1.[Na+] | ||
| 分子式 | C18H23N9NaO10P | 分子量 | 579.39 |
| 溶解度 | DMSO: 50 mg/mL (86.30 mM); Water | 储存条件 | Store at -20°C |
| General tips | 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°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.726 mL | 8.6298 mL | 17.2595 mL |
| 5 mM | 0.3452 mL | 1.726 mL | 3.4519 mL |
| 10 mM | 0.1726 mL | 0.863 mL | 1.726 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Guadecitabine (SGI-110): an investigational drug for the treatment of myelodysplastic syndrome and acute myeloid leukemia
Expert Opin Investig Drugs2019 Oct;28(10):835-849.PMID: 31510809DOI: 10.1080/13543784.2019.1667331
Introduction: The incidence of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) is increasing with the aging population. Prognosis and overall survival (OS) remain poor in elderly patients and in those not eligible for intensive treatment. Hypomethylating agents (HMAs) have played an important role in this group of patients but their efficacy is limited. Areas covered: This article reviews the mechanism of action, pharmacology, safety profile and clinical efficacy of subcutaneous guadecitabine, a second-generation DNA methylation inhibitor in development for the treatment of AML and MDS. Expert opinion: Although guadecitabine did not yield improved complete remission (CR) rates and OS compared to the control arm in patients with treatment-naïve AML who were ineligible for intensive chemotherapy, subgroup analysis in patients who received ≥4 cycles of therapy demonstrated superior outcomes in favor of guadecitabine. Given its stability, ease of administration, safety profile and prolonged exposure time, guadecitabine would be the more appropriate HMA, replacing azacitidine and decitabine, to be used combination treatment regimens in patients with myeloid malignancies.
Guadecitabine Plus Ipilimumab in Unresectable Melanoma: The NIBIT-M4 Clinical Trial
Clin Cancer Res2019 Dec 15;25(24):7351-7362.PMID: 31530631DOI: 10.1158/1078-0432.CCR-19-1335
Purpose: The immunomodulatory activity of DNA hypomethylating agents (DHAs) suggests they may improve the effectiveness of cancer immunotherapies. The phase Ib NIBIT-M4 trial tested this hypothesis using the next-generation DHA guadecitabine combined with ipilimumab.
Patients and methods: Patients with unresectable stage III/IV melanoma received escalating doses of guadecitabine 30, 45, or 60 mg/m2/day subcutaneously on days 1 to 5 every 3 weeks, and ipilimumab 3 mg/kg intravenously on day 1 every 3 weeks, starting 1 week after guadecitabine, for four cycles. Primary endpoints were safety, tolerability, and MTD of treatment; secondary were immune-related (ir) disease control rate (DCR) and objective response rate (ORR); and exploratory were changes in methylome, transcriptome, and immune contextures in sequential tumor biopsies, and pharmacokinetics.
Results: Nineteen patients were treated; 84% had grade 3/4 adverse events, and neither dose-limiting toxicities per protocol nor overlapping toxicities were observed. Ir-DCR and ir-ORR were 42% and 26%, respectively. Median CpG site methylation of tumor samples (n = 8) at week 4 (74.5%) and week 12 (75.5%) was significantly (P < 0.05) lower than at baseline (80.3%), with a median of 2,454 (week 4) and 4,131 (week 12) differentially expressed genes. Among the 136 pathways significantly (P < 0.05; Z score >2 or ←2) modulated by treatment, the most frequently activated were immune-related. Tumor immune contexture analysis (n = 11) demonstrated upregulation of HLA class I on melanoma cells, an increase in CD8+, PD-1+ T cells and in CD20+ B cells in posttreatment tumor cores.
Conclusions: Treatment of guadecitabine combined with ipilimumab is safe and tolerable in advanced melanoma and has promising immunomodulatory and antitumor activity.
Guadecitabine in myelodysplastic syndromes: promising but there is still progress to be made
Lancet Haematol2019 Jun;6(6):e290-e291.PMID: 31060978DOI: 10.1016/S2352-3026(19)30079-1
Purpose The objective of this mass balance trial was to determine the excretory pathways and metabolic profile of the novel anticancer agent guadecitabine in humans after administration of a 14C-radiolabeled dose of guadecitabine. Experimental design Included patients received at least one cycle of 45 mg/m2 guadecitabine subcutaneously as once-daily doses on Days 1 to 5 of a 28-day cycle, of which the 5th (last) dose in the first cycle was spiked with 14C-radiolabeled guadecitabine. Using different mass spectrometric techniques in combination with off-line liquid scintillation counting, the exposure and excretion of 14C-guadecitabine and metabolites in the systemic circulation, excreta, and intracellular target site were established. Results Five patients were enrolled in the mass balance trial. 14C-guadecitabine radioactivity was rapidly and almost exclusively excreted in urine, with an average amount of radioactivity recovered of 90.2%. After uptake in the systemic circulation, guadecitabine was converted into ß-decitabine (active anomer), and from ß-decitabine into the presumably inactive metabolites M1-M5. All identified metabolites in plasma and urine were ß-decitabine related products, suggesting almost complete conversion via cleavage of the phosphodiester bond between ß-decitabine and deoxyguanosine prior to further elimination. ß-decitabine enters the intracellular activation pathway, leading to detectable ß-decitabine-triphosphate and DNA incorporated ß-decitabine levels in peripheral blood mononuclear cells, providing confirmation that the drug reaches its DNA target site. Conclusion The metabolic and excretory pathways of guadecitabine and its metabolites were successfully characterized after subcutaneous guadecitabine administration in cancer patients. These data support the clinical evaluation of safety and efficacy of the subcutaneous guadecitabine drug product.
Mass balance and metabolite profiling of 14 C-guadecitabine in patients with advanced cancer
Invest New Drugs2020 Aug;38(4):1085-1095.PMID: 31605293DOI: 10.1007/s10637-019-00854-9
Purpose The objective of this mass balance trial was to determine the excretory pathways and metabolic profile of the novel anticancer agent guadecitabine in humans after administration of a 14C-radiolabeled dose of guadecitabine. Experimental design Included patients received at least one cycle of 45 mg/m2 guadecitabine subcutaneously as once-daily doses on Days 1 to 5 of a 28-day cycle, of which the 5th (last) dose in the first cycle was spiked with 14C-radiolabeled guadecitabine. Using different mass spectrometric techniques in combination with off-line liquid scintillation counting, the exposure and excretion of 14C-guadecitabine and metabolites in the systemic circulation, excreta, and intracellular target site were established. Results Five patients were enrolled in the mass balance trial. 14C-guadecitabine radioactivity was rapidly and almost exclusively excreted in urine, with an average amount of radioactivity recovered of 90.2%. After uptake in the systemic circulation, guadecitabine was converted into ß-decitabine (active anomer), and from ß-decitabine into the presumably inactive metabolites M1-M5. All identified metabolites in plasma and urine were ß-decitabine related products, suggesting almost complete conversion via cleavage of the phosphodiester bond between ß-decitabine and deoxyguanosine prior to further elimination. ß-decitabine enters the intracellular activation pathway, leading to detectable ß-decitabine-triphosphate and DNA incorporated ß-decitabine levels in peripheral blood mononuclear cells, providing confirmation that the drug reaches its DNA target site. Conclusion The metabolic and excretory pathways of guadecitabine and its metabolites were successfully characterized after subcutaneous guadecitabine administration in cancer patients. These data support the clinical evaluation of safety and efficacy of the subcutaneous guadecitabine drug product.