FX-11 (LDHA Inhibitor FX11)
(Synonyms: LDHA Inhibitor FX11) 目录号 : GC34011
FX-11（LDHA 抑制剂 FX11）被发现是一种有效的竞争性人 LDH-A 的 NADH 结合口袋抑制剂。
Cas No.:213971-34-7
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >97.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| Cell experiment [1]: | |
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Cell lines |
PC3 and DU145 (prostate carcinoma) cell lines |
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Preparation Method |
PC3 and DU145 cells maintained in log phase growth were plated in 96-well plates and treated with 0.25, 0.5, 1.5, 5, 15, 30, 60, 120, and 240 µmol/L FX-11 for 24 hours. |
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Reaction Conditions |
0.25, 0.5, 1.5, 5, 15, 30, 60, 120, and 240 µmol/L for 24 hours |
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Applications |
After treated with FX-11, the metabolic phenotype of the two cell lines in vitro demonstrated no significant difference in extracellular acidification rate (ECAR), oxygen consumption rate (OCR), pyruvate uptake, and lactate production. |
| Animal experiment [2]: | |
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Animal models |
male SCID mice |
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Preparation Method |
groups of five mice were injected with control 2% (vol/vol) DMSO or 42 µg of FX11 |
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Dosage form |
Intraperitoneal injection, 42µg daily, for 10 days |
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Applications |
Daily i.p. injection of 42 µg of FX11 also resulted in a remarkable inhibition of tumor growth. |
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References: [1]: Scroggins BT, Matsuo M, White AO, et al.. Hyperpolarized [1-13C]-pyruvate magnetic resonance spectroscopic imaging of prostate cancer In Vivo predicts efficacy of targeting the Warburg effect. Clin Cancer Res 2018;24(13):3137-3148. |
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FX-11 (LDHA Inhibitor FX11) was found to be a potent, competitive inhibitor of the human LDH-A's NADH binding pocket [1]. FX-11 was recharacterized using purified human liver LDHA with Ki of 8μM [2] FX11 inhibition of LDHA increased nonproductive mitochondrial respiration, leading to decreased ATP levels and cell proliferation, and increased oxygen consumption, ROS production and cell death [5].
FX-11 (IC50) for proliferation of DU145 and PC3 (prostate carcinoma) cell lines in vitro was strikingly similar (32 ± 1.1 μmol/L vs. 27 ± 1.1 μmol/L, respectively) [3]. Low concentrations of FX-11 could markedly decrease cell viability in the MPS2(the glycolytic subtype with upregulated carbohydrate and nucleotide metabolism) PDO (Patient-derived organoid) models [4].
FX-11, effectively inhibited tumor growth in human B-lymphoma and pancreatic cancer xenograft models. FX-11 could inhibit tumor growth in P493 lymphomas and human P198 pancreatic tumors ≥200 mm3 [5].
References:
[1]. EC Calvaresi. Small molecule inhibitors of lactate dehydrogenase a as an anticancer strategy. 2014.
[2]: Le, A. et al. Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression. Proc. Natl Acad. Sci. USA 107, 2037-2042 (2010).
[3]. Scroggins BT, Matsuo M, White AO, et al. Hyperpolarized [1-13C]-pyruvate magnetic resonance spectroscopic imaging of prostate cancer In Vivo predicts efficacy of targeting the Warburg effect. Clin Cancer Res 2018;24(13):3137-3148.
[4]. Gong Y, Ji P, Yang Y-S, Xie S, Yu T-J, Xiao Y, et al. Metabolic-Pathway-Based Subtyping of Triple-Negative Breast Cancer Reveals Potential Therapeutic Targets. Cell Metab (2021) 33:51-64.e9. doi: 10.1016/j.cmet.2020.10.012
[5]. P. Miao, S. Sheng, X. Sun, J. Liu, G. Huang.Lactate dehydrogenase A in cancer: a promising target for diagnosis and therapy. IUBMB Life, 65 (11) (2013), pp. 904-910
FX-11（LDHA 抑制剂 FX11）被发现是一种有效的竞争性人 LDH-A 的 NADH 结合口袋抑制剂[1]。使用 Ki 为 8μM [2] 的纯化人肝 LDHA 对 FX-11 进行了重新表征。细胞死亡[5].
FX-11 (IC50) 对于 DU145 和 PC3（前列腺癌）细胞系的体外增殖非常相似（分别为 32 ± 1.1 μmol/L 和 27 ± 1.1 μmol/L）[3] 。低浓度的 FX-11 可显着降低 MPS2（碳水化合物和核苷酸代谢上调的糖酵解亚型）PDO（患者来源的类器官）模型中的细胞活力[4]。
FX-11,有效抑制人 B 淋巴瘤和胰腺癌异种移植模型中的肿瘤生长。 FX-11可抑制P493淋巴瘤和人P198胰腺肿瘤≥200 mm3的肿瘤生长[5]。
| Cas No. | 213971-34-7 | SDF | |
| 别名 | LDHA Inhibitor FX11 | ||
| Canonical SMILES | O=C(C1=C2C=C(CC3=CC=CC=C3)C(C)=CC2=C(CCC)C(O)=C1O)O | ||
| 分子式 | C22H22O4 | 分子量 | 350.41 |
| 溶解度 | DMSO: 250 mg/mL (713.45 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 | 2.8538 mL | 14.269 mL | 28.538 mL |
| 5 mM | 0.5708 mL | 2.8538 mL | 5.7076 mL |
| 10 mM | 0.2854 mL | 1.4269 mL | 2.8538 mL |
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| 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 |
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| % 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，
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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。
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4-OI Protects MIN6 Cells from Oxidative Stress Injury by Reducing LDHA-Mediated ROS Generation
Biomolecules2022 Sep 4;12(9):1236.PMID: 36139075DOI: 10.3390/biom12091236
Pancreatic beta cells are highly susceptible to oxidative stress, which plays a crucial role in diabetes outcomes. Progress has been slow to identify molecules that could be utilized to enhance cell survival and function under oxidative stress. Itaconate, a byproduct of the tricarboxylic acid cycle, has both anti-inflammatory and antioxidant properties. The effects of itaconate on beta cells under oxidative stress are relatively unknown. We explored the effects of 4-octyl itaconate-a cell-permeable derivative of itaconate-on MIN6 (a beta cell model) under oxidative stress conditions caused by hypoxia, along with its mechanism of action. Treatment with 4-OI reversed hypoxia-induced cell death, reduced ROS production, and inhibited cell death pathway activation and inflammatory cytokine secretion in MIN6 cells. The 4-OI treatment also suppressed lactate dehydrogenase A (LDHA)activity, which increases under hypoxia. Treatment of cells with the ROS scavenger NAC and LDHA-specific inhibitor FX-11 reproduced the beneficial effects of 4-OI on MIN6 cell viability under oxidative stress conditions, confirming its role in regulating ROS production. Conversely, overexpression of LDHA reduced the beneficial effects exerted by 4-OI on cells. Our findings provide a strong rationale for using 4-OI to prevent the death of MIN6 cells under oxidative stress.
Targeting Pyruvate Kinase M2 and Lactate Dehydrogenase A Is an Effective Combination Strategy for the Treatment of Pancreatic Cancer
Cancers (Basel)2019 Sep 16;11(9):1372.PMID: 31527446DOI: 10.3390/cancers11091372
Reprogrammed glucose metabolism is one of the hallmarks of cancer, and increased expression of key glycolytic enzymes, such as pyruvate kinase M2 (PKM2) and lactate dehydrogenase A (LDHA), has been associated with poor prognosis in various malignancies. Targeting these enzymes could attenuate aerobic glycolysis and inhibit tumor proliferation. We investigated whether the PKM2 activator, TEPP-46, and the LDHA inhibitor, FX-11, can be combined to inhibit in vitro and in vivo tumor growth in preclinical models of pancreatic cancer. We assessed PKM2 and LDHA expression, enzyme activity, and cell proliferation rate after treatment with TEPP-46, FX-11, or a combination of both. Efficacy was validated in vivo by evaluating tumor growth, PK and LDHA activity in plasma and tumors, and PKM2, LDHA, and Ki-67 expression in tumor tissues following treatment. Dual therapy synergistically inhibited pancreatic cancer cell proliferation and significantly delayed tumor growth in vivo without apparent toxicity. Treatment with TEPP-46 and FX-11 resulted in increased PK and reduced LDHA enzyme activity in plasma and tumor tissues and decreased PKM2 and LDHA expression in tumors, which was reflected by a decrease in tumor volume and proliferation. The targeting of glycolytic enzymes such as PKM2 and LDHA represents a promising therapeutic approach for the treatment of pancreatic cancer.
Proteomic identification of the lactate dehydrogenase A in a radioresistant prostate cancer xenograft mouse model for improving radiotherapy
Oncotarget2016 Nov 8;7(45):74269-74285.PMID: 27708237DOI: 10.18632/oncotarget.12368
Radioresistance is a major challenge for prostate cancer (CaP) metastasis and recurrence after radiotherapy. This study aimed to identify potential protein markers and signaling pathways associated with radioresistance using a PC-3 radioresistant (RR) subcutaneous xenograft mouse model and verify the radiosensitization effect from a selected potential candidate. PC-3RR and PC-3 xenograft tumors were established and differential protein expression profiles from two groups of xenografts were analyzed using liquid chromatography tandem-mass spectrometry. One selected glycolysis marker, lactate dehydrogenase A (LDHA) was validated, and further investigated for its role in CaP radioresistance. We found that 378 proteins and 51 pathways were significantly differentially expressed between PC-3RR and PC-3 xenograft tumors, and that the glycolysis pathway is closely linked with CaP radioresistance. In addition, we also demonstrated that knock down of LDHA with siRNA or inhibition of LDHA activity with a LDHA specific inhibitor (FX-11), could sensitize PC-3RR cells to radiotherapy with reduced epithelial-mesenchymal transition, hypoxia, DNA repair ability and autophagy, as well as increased DNA double strand breaks and apoptosis. In summary, we identified a list of potential RR protein markers and important signaling pathways from a PC-3RR xenograft mouse model, and demonstrate that targeting LDHA combined with radiotherapy could increase radiosensitivity in RR CaP cells, suggesting that LDHA is an ideal therapeutic target to develop combination therapy for overcoming CaP radioresistance.