FB23
目录号 : GC60833
FB23 is a potent and selective inhibitor of FTO demethylase with IC50 of 60 nM. FB23 directly binds to FTO and selectively inhibits FTO's mRNA N6-methyladenosine (m6A) demethylase activity.
Cas No.:2243736-35-6
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >99.00%
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- SDS (Safety Data Sheet)
- Datasheet
FB23 is a potent and selective inhibitor of FTO demethylase with IC50 of 60 nM. FB23 directly binds to FTO and selectively inhibits FTO's mRNA N6-methyladenosine (m6A) demethylase activity.
FB23 treatment inhibits acute myeloid leukemia (AML) cells proliferation with IC50 values of 44.8 μM, 23.6 μM for NB4 and MONOMAC6 AML cells. FB23 treatment causes the significant suppression of MYC targets, E2F targets, and G2M checkpoint signal cascades, which may contribute to the inhibitory effects of FTO inhibitors and FTO KD on cell cycle and proliferation. FB23 treatments activates apoptosis and p53 pathways.[1]
Pharmacological inhibition of FTO by FB23-2 substantially suppresses leukemia progression and prolongs survival.[1]
[1] Yue Huang, et al. Cancer Cell. 2019 Apr 15;35(4):677-691.e10.
| Cas No. | 2243736-35-6 | SDF | |
| Canonical SMILES | O=C(O)C1=CC=CC=C1NC2=C(Cl)C=C(C3=C(C)ON=C3C)C=C2Cl | ||
| 分子式 | C18H14Cl2N2O3 | 分子量 | 377.22 |
| 溶解度 | DMSO: 125 mg/mL (331.37 mM) | 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 | 2.651 mL | 13.2549 mL | 26.5097 mL |
| 5 mM | 0.5302 mL | 2.651 mL | 5.3019 mL |
| 10 mM | 0.2651 mL | 1.3255 mL | 2.651 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。
Small-Molecule Targeting of Oncogenic FTO Demethylase in Acute Myeloid Leukemia
Cancer Cell 2019 Apr 15;35(4):677-691.e10.PMID:30991027DOI:10.1016/j.ccell.2019.03.006.
FTO, an mRNA N6-methyladenosine (m6A) demethylase, was reported to promote leukemogenesis. Using structure-based rational design, we have developed two promising FTO inhibitors, namely FB23 and FB23-2, which directly bind to FTO and selectively inhibit FTO's m6A demethylase activity. Mimicking FTO depletion, FB23-2 dramatically suppresses proliferation and promotes the differentiation/apoptosis of human acute myeloid leukemia (AML) cell line cells and primary blast AML cells in vitro. Moreover, FB23-2 significantly inhibits the progression of human AML cell lines and primary cells in xeno-transplanted mice. Collectively, our data suggest that FTO is a druggable target and that targeting FTO by small-molecule inhibitors holds potential to treat AML.
The m6A demethylase FTO promotes the osteogenesis of mesenchymal stem cells by downregulating PPARG
Acta Pharmacol Sin 2022 May;43(5):1311-1323.PMID:PMC9061799DOI:10.1038/s41401-021-00756-8.
N6-methyladenosine (m6A) is the most abundant posttranscriptional methylation modification that occurs in mRNA and modulates the fine-tuning of various biological processes in mammalian development and human diseases. In this study we investigated the role of m6A modification in the osteogenesis of mesenchymal stem cells (MSCs), and the possible mechanisms by which m6A modification regulated the processes of osteoporosis and bone necrosis. We performed systematic analysis of the differential gene signatures in patients with osteoporosis and bone necrosis and conducted m6A-RNA immunoprecipitation (m6A-RIP) sequencing to identify the potential regulatory genes involved in osteogenesis. We showed that fat mass and obesity (FTO), a primary m6A demethylase, was significantly downregulated in patients with osteoporosis and osteonecrosis. During the differentiation of human MSCs into osteoblasts, FTO was markedly upregulated. Both depletion of FTO and application of the FTO inhibitor FB23 or FB23-2 impaired osteogenic differentiation of human MSCs. Knockout of FTO in mice resulted in decreased bone mineral density and impaired bone formation. PPARG, a biomarker for osteoporosis, was identified as a critical downstream target of FTO. We further revealed that FTO mediated m6A demethylation in the 3'UTR of PPARG mRNA, and reduced PPARG mRNA stability in an YTHDF1-dependent manner. Overexpression of PPARG alleviated FTO-mediated osteogenic differentiation of MSCs, whereas knockdown of PPARG promoted FTO-induced expression of the osteoblast biomarkers ALPL and OPN during osteogenic differentiation. Taken together, this study demonstrates the functional significance of the FTO-PPARG axis in promoting the osteogenesis of human MSCs and sheds light on the role of m6A modification in mediating osteoporosis and osteonecrosis.
Structure-Activity Relationships and Antileukemia Effects of the Tricyclic Benzoic Acid FTO Inhibitors
J Med Chem 2022 Aug 11;65(15):10638-10654.PMID:35793358DOI:10.1021/acs.jmedchem.2c00848.
The N6-methyladenosine (m6A) demethylase FTO is overexpressed in acute myeloid leukemia (AML) cells and promotes leukemogenesis. We previously developed tricyclic benzoic acid FB23 as a highly potent FTO inhibitor in vitro. However, it showed a moderate antiproliferative effect on AML cells. In this work, we performed a structure-activity relationship study of tricyclic benzoic acids as FTO inhibitors. The analog 13a exhibited excellent inhibitory effects on FTO similar to that of FB23 in vitro. In contrast to FB23, 13a exerted a strong antiproliferative effect on AML cells. Like FTO knock down, 13a upregulated ASB2 and RARA expression and increased the protein abundance while it downregulated MYC expression and decreased MYC protein abundance. These genes are key FTO targets in AML cells. Finally, 13a treatment improved the survival rate of MONOMAC6-transplanted NSG mice. Collectively, our data suggest that targeting FTO with tricyclic benzoic acid inhibitors may be a potential strategy for treating AML.
Curcuminoids attenuate myocardial ischemia-reperfusion injury by regulating total RNA m6A levels: in vitro study
Comb Chem High Throughput Screen 2022 Sep 29.PMID:36177634DOI:10.2174/1386207325666220929141003.
Objective: Myocardial ischemia-reperfusion (IR) injury is an unresolved medical problem with a high incidence. This study aims to analyze the novel molecular mechanism by which curcuminoids protect cardiomyocytes from IR injury. Methods: A IR model in vitro of rat cardiomyocytes H9c2 cells was structured. Curcumin (CUR) and its derivatives, demethoxycurcumin (DMC) and bisdemethoxycurcumin (BDMC) treated H9c2 cells, and reactive oxygen species (ROS) production, viability, apoptosis, mitochondrial membrane potential (MMP), oxidative stress and total RNA m6A levels of H9c2 cells were detected by using DCFH-DA stain, CCK-8, flow cytometry, Hoechst 33342 stain, TMRM stain, ELISA and RT-qPCR. FB23 was used in rescue experiments. Results: IR significantly increased ROS production, decreased cell viability, and induced apoptosis, MMP loss, and oxidative stress. In addition, IR induced an increase in total RNA m6A levels and changes in m6A-related proteins expression. CUR (10 μM), DMC (10 μM) and BDMC (10 μM), significantly inhibited IR-induced ROS production, apoptosis, MMP loss and oxidative stress, and enhanced cell viability. Furthermore, CUR, DMC and BDMC altered the expression pattern of m6A-related proteins and reduced IR-induced total m6A levels. There was no significant difference in the effects of the three. FB23 partially offseted the protective effect of CUR. Conclusion：Curcuminoids attenuate myocardial IR injury by regulating total RNA m6A levels.
The Yin and Yang of RNA Methylation: An Imbalance of Erasers Enhances Sensitivity to FTO Demethylase Small-Molecule Targeting in Leukemia Stem Cells
Cancer Cell 2019 Apr 15;35(4):540-541.PMID:30991023DOI:10.1016/j.ccell.2019.03.011.
A prevalent eukaryotic N6-methyladensosine (m6A) post-transcriptional mark can be "erased" by the m6A demethylase FTO, which is commonly deregulated in acute myeloid leukemia (AML). In this issue of Cancer Cell, Huang et al. design small-molecule FTO inhibitors, FB23 and FB23-2, and demonstrate their potent inhibitory impact in AML models.