Dac51
目录号 : GC25331Dac51 is a potent FTO inhibitor with an IC50 of 0.4 μM for inhibiting FTO demethylation.
Cas No.:2243944-92-3 (free base)
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
Dac51 is a potent FTO inhibitor with an IC50 of 0.4 μM for inhibiting FTO demethylation.
Dac51 can serve as a potent FTO inhibitor to dampen the glycolytic capacity of tumor cells by inhibiting FTO-mediated demethylation on transcripts including Jun and Cebpb.[1]
Dac51, a FTO inhibitor, delivers strong T cell-mediated antitumor effects and prevents tumor recurrence via increasesing CD8+ T cell in?ltration in tumors, in multiple vivo cancer models.[1]
[1] Yi Liu, et al. Cell Metab. 2021 Jun 1;33(6):1221-1233.e11.
| Cas No. | 2243944-92-3 (free base) | SDF | Download SDF |
| 分子式 | C20H17Cl2F3N4O4 | 分子量 | 505.27 |
| 溶解度 | DMSO: 100 mg/mL (197.91 mM);Water: Insoluble;Ethanol: Insoluble | 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 | 1.9791 mL | 9.8957 mL | 19.7914 mL |
| 5 mM | 0.3958 mL | 1.9791 mL | 3.9583 mL |
| 10 mM | 0.1979 mL | 0.9896 mL | 1.9791 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。
Tumors exploit FTO-mediated regulation of glycolytic metabolism to evade immune surveillance
Cell Metab 2021 Jun 1;33(6):1221-1233.e11.PMID:33910046DOI:10.1016/j.cmet.2021.04.001.
The ever-increasing understanding of the complexity of factors and regulatory layers that contribute to immune evasion facilitates the development of immunotherapies. However, the diversity of malignant tumors limits many known mechanisms in specific genetic and epigenetic contexts, manifesting the need to discover general driver genes. Here, we have identified the m6A demethylase FTO as an essential epitranscriptomic regulator utilized by tumors to escape immune surveillance through regulation of glycolytic metabolism. We show that FTO-mediated m6A demethylation in tumor cells elevates the transcription factors c-Jun, JunB, and C/EBPβ, which allows the rewiring of glycolytic metabolism. Fto knockdown impairs the glycolytic activity of tumor cells, which restores the function of CD8+ T cells, thereby inhibiting tumor growth. Furthermore, we developed a small-molecule compound, Dac51, that can inhibit the activity of FTO, block FTO-mediated immune evasion, and synergize with checkpoint blockade for better tumor control, suggesting reprogramming RNA epitranscriptome as a potential strategy for immunotherapy.
NR3C1/Glucocorticoid receptor activation promotes pancreatic β-cell autophagy overload in response to glucolipotoxicity
Autophagy 2023 Apr 20;1-20.PMID:37039556DOI:10.1080/15548627.2023.2200625.
Diabetes is a complex and heterogeneous disorder characterized by chronic hyperglycemia. Its core cause is progressively impaired insulin secretion by pancreatic β-cell failures, usually upon a background of preexisting insulin resistance. Recent studies demonstrate that macroautophagy/autophagy is essential to maintain architecture and function of β-cells, whereas excessive autophagy is also involved in β-cell dysfunction and death. It has been poorly understood whether autophagy plays a protective or harmful role in β-cells, while we report here that it is dependent on NR3C1/glucocorticoid receptor activation. We proved that deleterious hyperactive autophagy happened only upon NR3C1 activation in β-cells under glucolipotoxic conditions, which eventually promoted diabetes. The transcriptome and the N6-methyladenosine (m6A) methylome revealed that NR3C1-enhancement upregulated the RNA demethylase FTO (fat mass and obesity associated) protein in β-cells, which caused diminished m6A modifications on mRNAs of four core Atg (autophagy related) genes (Atg12, Atg5, Atg16l2, Atg9a) and, hence, hyperactive autophagy and defective insulin output; by contrast, FTO inhibition, achieved by the specific FTO inhibitor Dac51, prevented NR3C1-instigated excessive autophagy activation. Importantly, Dac51 effectively alleviated impaired insulin secretion and glucose intolerance in hyperglycemic β-cell specific NR3C1 overexpression mice. Our results determine that the NR3C1-FTO-m6A modifications-Atg genes axis acts as a key mediator of balanced autophagic flux in pancreatic β-cells, which offers a novel therapeutic target for the treatment of diabetes.Abbreviations: 3-MA: 3-methyladenine; AAV: adeno-associated virus; Ac: acetylation; Ad: adenovirus; AL: autolysosome; ATG: autophagy related; AUC: area under curve; Baf A1: bafilomycin A1; βNR3C1 mice: pancreatic β-cell-specific NR3C1 overexpression mice; cFBS: charcoal-stripped FBS; Ctrl: control; ER: endoplasmic reticulum; FTO: fat mass and obesity associated; GC: glucocorticoid; GRE: glucocorticoid response element; GSIS: glucose-stimulated insulin secretion assay; HFD: high-fat diet; HG: high glucose; HsND: non-diabetic human; HsT2D: type 2 diabetic human; i.p.: intraperitoneal injected; KSIS: potassium-stimulated insulin secretion assay; m6A: N6-methyladenosine; MeRIP-seq: methylated RNA immunoprecipitation sequencing; NR3C1/GR: nuclear receptor subfamily 3, group C, member 1; NR3C1-Enhc.: NR3C1-enhancement; NC: negative control; Palm.: palmitate; RNA-seq: RNA sequencing; T2D: type 2 diabetes; TEM: transmission electron microscopy; UTR: untranslated region; WT: wild-type.