OSMI-1
目录号 : GC14870
An OGT inhibitor
Cas No.:1681056-61-0
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| Cell experiment [1]: | |
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Cell lines |
Tamoxifen-sensitive (TamS) and tamoxifen-resistant (TamR) MCF7 breast cancer cells |
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Preparation Method |
TamS and TamR cells were collected on ice following 24 h of treatment with 40 µM dose of OSMI-1 compound, or DMSO. Samples were immediately fixed in 100% ice-cold methanol and placed in - 20 °C for storage. Samples were washed in cold PBS and stained with 1.5 µg/ml Hoechst 33258 in PBS for 30 min at 37 °C. Cell cycle analysis was then performed on LSR II flow cytometer. |
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Reaction Conditions |
40 µM for 24 h |
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Applications |
OSMI-1 decreased the number of cells in S-Phase and also caused a modest, but not significant, accumulation of cells in the G2-M phase |
| Animal experiment [2]: | |
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Animal models |
HCT116 xenograft models on Five-week-old female BALB/c-Foxn1nu/ArcGem nude mice |
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Preparation Method |
HCT116 xenograft models were injected subcutaneously with 5 × 106 cells in the flanks of each mouse. After 7 days, tumor-bearing mice (tumor volume approximately 90-110 mm3) were randomized into various treatment groups (n = 4/group) as follows: Group 1—mice were administered DMSO as a vehicle control; Group 2—mice were administered TRAIL (500 µg/kg/daily, Intraperitoneal); Group 3—mice were administered OSMI-1(1 mg/kg/daily, Intravenous); Group 4—mice were coadministered TRAIL and OSMI-1 for 21 consecutive days. |
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Dosage form |
1 mg/kg/daily, i.v. |
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Applications |
The tumor size in mice treated with TRAIL or OSMI-1 alone was slightly reduced compared with the control group but was significantly reduced (5-fold) in the TRAIL and OSMI-1 combination group. |
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References: [1]: Barkovskaya A, Seip K, Prasmickaite L, et al. Inhibition of O-GlcNAc transferase activates tumor-suppressor gene expression in tamoxifen-resistant breast cancer cells[J]. Scientific reports, 2020, 10(1): 1-10. |
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OSMI-1 is an O-GlcNAc transferase (OGT) small molecule inhibitor that does not significantly affect other glycosyltransferases [1]. OSMI-1 inhibited full length human OGT (ncOGT) with an IC50 value of 2.7 µM [2].
OSMI-1 ranging from 10 to 100 µM treated inhibited global O-GlcNAcylation in Chinese hamster ovary (CHO) cells with the maximal effect being achieved at 50 µM [2]. 50 µM OSMI-1 treated CHO cells decreased viability by about 50% after 24 h [2]. OSMI-1 (40 µM) decreased total-O-GlcNAc by 30% in both TamS and TamR cells lines [1]. TamR cells were significantly more sensitive to OSMI-1 than the parental TamS cells, with OSMI-1-EC50 value of ~15 µM in TamR and ~ 40 µM in TamS by activity for proliferation assay [1]. OSMI-1 (40 µM, 24 h) increased expression of OGT and DDIT3 in both TamS and TamR cells while ERα is downregulated [1]. The levels of intracellular and secreted HBsAg, but not HBeAg, in the supernatants increased in primary human hepatocytes (PHHs) and HepG2.2.15 cells after OSMI-1 treatment [3].
OSMI-1 reduced osteoclast differentiation in vivo by disrupting the translocation of NF-κB p65 and nuclear factor of activated T cells c1 (NFATc1) into the nucleus by controlling their PTM O-GlcNAcylation. OSMI-1 treatment effectively inhibited lipopolysaccharide (LPS)-induced formation of TRAP-positive osteoclasts in the cavarial surface compared to the mice injected with the vehicle, while OSMI-1 significantly reduced the number of TRAP-specific mature osteoclasts in the calvarial surfaces and sections [4]. The tumor size in mice treated with TRAIL or OSMI-1 alone was slightly reduced compared with the control group but was significantly reduced (5-fold) in the TRAIL and OSMI-1 combination group on HCT116 Xenograft in Nude Mice. Compared with vehicle-treated xenograft mice, the levels of ER stress-related proteins, such as IRE1α, PERK, p-JNK, CHOP and DR5, were increased when either TRAIL or OSMI-1 was administered alone, whereas these effects were even greater for the combination treatment [5].
OSMI-1是一种O-GlcNAc转移酶（OGT）小分子抑制剂，不会显著影响其他糖基转移酶[1]。OSMI-1抑制全长人OGT（ncOGT），IC50值为2.7µM[2]。
10至100µM的OSMI-1处理抑制了中国仓鼠卵巢（CHO）细胞的整体O-GlcNAcylation，在50µM时达到最大效果[2]。50µM OSMI-1处理的CHO细胞在24小时后活力降低约50%[2]。OSMI-1（40µM）使TamS和TamR细胞系中的总-O-GlcNAc降低了30%[1]。TamR细胞对OSMI-1的敏感性明显高于亲代TamS细胞，通过增殖活性测定，TamR中OSMI-1-EC50值约为15µM，TamS中OSMI-1-EC50值为约40µM[1]。OSMI-1（40µM，24小时）增加了TamS和TamR细胞中OGT和DDIT3的表达，而ERα下调[1]。OSMI-1处理后，原代人肝细胞（PHHs）和HepG2.2.15细胞上清液中细胞内和分泌的HBsAg水平增加，但HBeAg水平没有增加[3]。
OSMI-1通过控制其PTM-O-GlcNAcylation，破坏NF-κB p65和活化T细胞核因子c1（NFATc1）向细胞核的易位，从而在体内减少破骨细胞分化。与注射载体的小鼠相比，OSMI-1治疗有效抑制了脂多糖（LPS）诱导的颅骨表面TRAP阳性破骨细胞的形成，而OSMI-1显著减少了颅骨表面和切片中TRAP特异性成熟破骨细胞数量[4]。与对照组相比，单独用TRAIL或OSMI-1处理的小鼠中的肿瘤大小略有减小，但在裸小鼠中的HCT116异种移植物上，TRAIL和OSMI-1组合组中的肿瘤尺寸显著减小（5倍）。与载体处理的异种移植物小鼠相比，当单独施用TRAIL或OSMI-1时，ER应激相关蛋白（如IRE1α、PERK、p-JNK、CHOP和DR5）的水平增加，而联合治疗的这些作用甚至更大[5]。
References:
[1]. Barkovskaya A, Seip K, Prasmickaite L, et al. Inhibition of O-GlcNAc transferase activates tumor-suppressor gene expression in tamoxifen-resistant breast cancer cells[J]. Scientific reports, 2020, 10(1): 1-10.
[2]. Ortiz-Meoz R F, Jiang J, Lazarus M B, et al. A small molecule that inhibits OGT activity in cells[J]. ACS chemical biology, 2015, 10(6): 1392-1397.
[3]. Wang X, Lin Y, Liu S, et al. O-GlcNAcylation modulates HBV replication through regulating cellular autophagy at multiple levels[J]. The FASEB Journal, 2020, 34(11): 14473-14489.
[4].Kim M J, Kim H S, Lee S, et al. Hexosamine Biosynthetic Pathway-Derived O-GlcNAcylation Is Critical for RANKL-Mediated Osteoclast Differentiation[J]. International Journal of Molecular Sciences, 2021, 22(16): 8888.
[5]. Lee S J, Lee D E, Choi S Y, et al. OSMI-1 enhances TRAIL-induced apoptosis through ER stress and NF-κB signaling in colon cancer cells[J]. International journal of molecular sciences, 2021, 22(20): 11073.
| Cas No. | 1681056-61-0 | SDF | |
| 化学名 | (R)-N-(furan-2-ylmethyl)-2-(2-methoxyphenyl)-2-(2-oxo-1,2-dihydroquinoline-6-sulfonamido)-N-(thiophen-2-ylmethyl)acetamide | ||
| Canonical SMILES | O=C(N(CC1=CC=CS1)CC2=CC=CO2)[C@H](NS(C3=CC(C=C4)=C(C=C3)NC4=O)(=O)=O)C5=CC=CC=C5OC | ||
| 分子式 | C28H25N3O6S2 | 分子量 | 563.64 |
| 溶解度 | 20mg/mL in DMSO, 25mg/mL in DMF | 储存条件 | Store at -20°C,protect from light |
| 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 | 1.7742 mL | 8.8709 mL | 17.7418 mL |
| 5 mM | 0.3548 mL | 1.7742 mL | 3.5484 mL |
| 10 mM | 0.1774 mL | 0.8871 mL | 1.7742 mL |
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动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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2.
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OSMI-1 Enhances TRAIL-Induced Apoptosis through ER Stress and NF-κB Signaling in Colon Cancer Cells
Levels of O-GlcNAc transferase (OGT) and hyper-O-GlcNAcylation expression levels are associated with cancer pathogenesis. This study aimed to find conditions that maximize the therapeutic effect of cancer and minimize tissue damage by combining an OGT inhibitor (OSMI-1) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). We found that OSMI-1 treatment in HCT116 human colon cancer cells has a potent synergistic effect on TRAIL-induced apoptosis signaling. Interestingly, OSMI-1 significantly increased TRAIL-mediated apoptosis by increasing the expression of the cell surface receptor DR5. ROS-induced endoplasmic reticulum (ER) stress by OSMI-1 not only upregulated CHOP-DR5 signaling but also activated Jun-N-terminal kinase (JNK), resulting in a decrease in Bcl2 and the release of cytochrome c from mitochondria. TRAIL induced the activation of NF-κB and played a role in resistance as an antiapoptotic factor. During this process, O-GlcNAcylation of IκB kinase (IKK) and IκBα degradation occurred, followed by translocation of p65 into the nucleus. However, combination treatment with OSMI-1 counteracted the effect of TRAIL-mediated NF-κB signaling, resulting in a more synergistic effect on apoptosis. Therefore, the combined treatment of OSMI-1 and TRAIL synergistically increased TRAIL-induced apoptosis through caspase-8 activation. Conclusively, OSMI-1 potentially sensitizes TRAIL-induced cell death in HCT116 cells through the blockade of NF-κB signaling and activation of apoptosis through ER stress response.
Hyperglycemia Acutely Increases Cytosolic Reactive Oxygen Species via O-linked GlcNAcylation and CaMKII Activation in Mouse Ventricular Myocytes
Rationale: Diabetes mellitus is a complex, multisystem disease, affecting large populations worldwide. Chronic CaMKII (Ca2+/calmodulin-dependent kinase II) activation may occur in diabetes mellitus and be arrhythmogenic. Diabetic hyperglycemia was shown to activate CaMKII by (1) O-linked attachment of N-acetylglucosamine (O-GlcNAc) at S280 leading to arrhythmia and (2) a reactive oxygen species (ROS)-mediated oxidation of CaMKII that can increase postinfarction mortality.
Objective: To test whether high extracellular glucose (Hi-Glu) promotes ventricular myocyte ROS generation and the role played by CaMKII.
Methods and results: We tested how extracellular Hi-Glu influences ROS production in adult ventricular myocytes, using DCF (2',7'-dichlorodihydrofluorescein diacetate) and genetically targeted Grx-roGFP2 redox sensors. Hi-Glu (30 mmol/L) significantly increased the rate of ROS generation-an effect prevented in myocytes pretreated with CaMKII inhibitor KN-93 or from either global or cardiac-specific CaMKIIδ KO (knockout) mice. CaMKII KO or inhibition also prevented Hi-Glu-induced sarcoplasmic reticulum Ca2+ release events (Ca2+ sparks). Thus, CaMKII activation is required for Hi-Glu-induced ROS generation and sarcoplasmic reticulum Ca2+ leak in cardiomyocytes. To test the involvement of O-GlcNAc-CaMKII pathway, we inhibited GlcNAcylation removal by Thiamet G (ThmG), which mimicked the Hi-Glu-induced ROS production. Conversely, inhibition of GlcNAcylation (OSMI-1 [(αR)-α-[[(1,2-dihydro-2-oxo-6-quinolinyl)sulfonyl]amino]-N-(2-furanylmethyl)-2-methoxy-N-(2-thienylmethyl)-benzeneacetamide]) prevented ROS induction in response to either Hi-Glu or ThmG. Moreover, in a CRSPR-based knock-in mouse in which the functional GlcNAcylation site on CaMKIIδ was ablated (S280A), neither Hi-Glu nor ThmG induced myocyte ROS generation. So CaMKIIδ-S280 is required for the Hi-Glu-induced (and GlcNAc dependent) ROS production. To identify the ROS source(s), we used different inhibitors of NOX (NADPH oxidase) 2 (Gp91ds-tat peptide), NOX4 (GKT137831), mitochondrial ROS (MitoTempo), and NOS (NO synthase) pathway inhibitors (L-NAME, L-NIO, and L-NPA). Only NOX2 inhibition or KO prevented Hi-Glu/ThmG-induced ROS generation.
Conclusions: Diabetic hyperglycemia induces acute cardiac myocyte ROS production by NOX2 that requires O-GlcNAcylation of CaMKIIδ at S280. This novel ROS induction may exacerbate pathological consequences of diabetic hyperglycemia.
REM Sleep Deprivation Impairs Learning and Memory by Decreasing Brain O-GlcNAc Cycling in Mouse
Rapid eye movement (REM) sleep is implicated learning and memory (L/M) functions and hippocampal long-term potentiation (LTP). Here, we demonstrate that REM sleep deprivation (REMSD)-induced impairment of contextual fear memory in mouse is linked to a reduction in hexosamine biosynthetic pathway (HBP)/O-GlcNAc flux in mouse brain. In mice exposed to REMSD, O-GlcNAcylation, and O-GlcNAc transferase (OGT) were downregulated while O-GlcNAcase was upregulated compared to control mouse brain. Foot shock fear conditioning (FC) induced activation of protein kinase A (PKA) and cAMP response element binding protein (CREB), which were significantly inhibited in brains of the REMSD group. Intriguingly, REMSD-induced defects in L/M functions and FC-induced PKA/CREB activation were restored upon increasing O-GlcNAc cycling with glucosamine (GlcN) or Thiamet G. Furthermore, Thiamet G restored the REMSD-induced decrease in dendritic spine density. Suppression of O-GlcNAcylation by the glutamine fructose-6-phosphate amidotransferase (GFAT) inhibitor, 6-diazo-5-oxo-L-norleucine (DON), or OGT inhibitor, OSMI-1, impaired memory function, and inhibited FC-induced PKA/CREB activation. DON additionally reduced the amplitude of baseline field excitatory postsynaptic potential (fEPSP) and magnitude of long-term potentiation (LTP) in normal mouse hippocampal slices. To our knowledge, this is the first study to provide comprehensive evidence of dynamic O-GlcNAcylation changes during the L/M process in mice and defects in this pathway in the brain of REM sleep-deprived mice. Our collective results highlight HBP/O-GlcNAc cycling as a novel molecular link between sleep and cognitive function.
O-GlcNAc Transferase Inhibitor Synergistically Enhances Doxorubicin-Induced Apoptosis in HepG2 Cells
The combination of chemotherapy with chemosensitizing agents is a common approach to enhance anticancer activity while reducing the dose-dependent adverse side effects of cancer treatment. Herein, we investigated doxorubicin (DOX) and O-GlcNAc transferase (OGT) inhibitor OSMI-1 combination treatment, which significantly enhanced apoptosis in hepatocellular carcinoma cells (HepG2) as a result of synergistic drug action in disparate stress signaling pathways. Treatment with a low dose of DOX or a suboptimal dose of OSMI-1 alone did not induce apoptotic cell death in HepG2 cells. However, the combination of DOX with OSMI-1 in HepG2 cells synergistically increased apoptotic cell death through the activation of both the p53 and mitochondrial Bcl2 pathways compared to DOX alone. We also demonstrated that the combination of DOX and OSMI-1 stimulated cell death, dramatically reducing cell proliferation and tumor growth in vivo using a HepG2 xenograft mouse model. These findings indicate that OSMI-1 acts as a potential chemosensitizer by enhancing DOX-induced cell death. This study provides insight into a possible mechanism of chemotherapy resistance, identifies potential novel drug targets, and suggests that OGT inhibition could be utilized in clinical applications to treat hepatocellular carcinoma as well as other cancer types.
Investigating the Impact of OGT Inhibition on Doxorubicin- and Docetaxel-Induced Cytotoxicity in PC-3 and WPMY-1 Cells
Reduction in sensitivity in terms of cytotoxicity is responsible for therapy failure in patients undergoing chemotherapy with first-line anticancer drug molecules. A plethora of literature evidence points out that increased O-linked β-N-acetylglucosamine transferase (OGT) enzyme level/hyper-O-GlcNAcylation has direct implications in development of cancer and interferes with clinical outcomes of chemotherapy via interaction with oncogenic factors. The aim of this research was to evaluate the combination approach of anticancer drugs with an OGT inhibitor (OSMI-1) as an alternative way to resolve issues in the treatment of prostate cancer and assess the benefits offered by this approach. Effect of combination of doxorubicin and docetaxel with OSMI-1 on drug-induced cell death and synergism/antagonism was investigated using resazurin assay. Reduction in OGT enzyme level was evaluated using ELISA kit. Caspase-3/7 fluorescence assay was performed to detect apoptosis induction in PC-3 cells after treatment with the combinations of doxorubicin and OGT inhibitor to further understand the mechanism of cell death by concomitant treatment. Studies reveal that combination approach is indeed effective in terms of reducing the half-maximum growth inhibition value of doxorubicin when concomitantly treated with OSMI-1 and has synergistic effect in prostate cancer cells. PC-3 cells exhibited elevated levels of OGT enzyme in comparison to WPMY-1, and OSMI-1 has potential to inhibit OGT enzyme significantly. Data show that OSMI-1 alone and in combination with doxorubicin reduces OGT enzyme level significantly accompanied by increased apoptosis in prostate cancer cells. Combination of doxorubicin with OSMI-1 reduced the elevated OGT level which led to a drastic increase in sensitivity of PC-3 cells toward doxorubicin in comparison to doxorubicin alone. This finding provides important insight regarding alternative treatment strategies for effective management of cancer.