KAN0438757
目录号 : GC36383
KAN0438757是一种有效的选择性代谢激酶PFKFB3抑制剂，IC50值为0.19 μM。
Cas No.:1451255-59-6
Sample solution is provided at 25 µL, 10mM.
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- Purity: >99.00%
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Cell experiment [1]: | |
Cell lines | HCT-116、HT-29、HUVECs、normal colon epithelial cells |
Preparation method | Cells were seeded into 96-well plates. After 24 h of incubation, the medium was replaced with 100 μL of medium containing different concentrations of KAN0438757(10, 25, 50, 100μM). Cell death was assessed within 48h. |
Reaction Conditions | 10, 25, 50, 100μM; 48 h |
Applications | KAN0438757 dose-dependently increased the cell death rates of HCT-116, HT-29, HUVECs, and normal colon epithelial cells, with less effect on normal colon epithelial cells. |
Animal experiment [2]: | |
Animal models | Wild-type C57BL/6 male mice |
Preparation method | Wild-type C57BL/6 male mice (8 weeks old), weighing 20-25 g, were randomly divided into groups (n=5) and fasted for 12h. The CAE-AP group was intraperitoneally injected with KAN0438757 (25mg/kg)+caerulein, and the FAEE-SAP group was intraperitoneally injected with KAN0438757 (25 mg/kg)+fatty acid ethyl ester. |
Dosage form | 25mg/kg; i.p. |
Applications | KAN0438757 inhibited the amylase level and apoptotic activity in the FAEE-SAP and CAE-AP group mice. |
References: | |
KAN0438757 is a potent and selective inhibitor of the metabolic kinase PFKFB3 with an IC50 value of 0.19μM[1]. PFKFB3 is an enzyme that plays a key role in glycolysis and is overexpressed in a variety of cancer cells[2]. KAN0438757 can also act as a selective inhibitor of PFKFB4[3].
In vitro, treatment of HCT-116, HT-29, HUVECs and normal colon epithelial cells with KAN0438757 (10-100μM) for 48 h increased cell death in a dose-dependent manner, but had little effect on normal colon epithelial cells[4]. Treatment of non-small cell lung cancer A549 cells with KAN0438757 (1-100μM) for 24-72 h significantly reduced cell viability, inhibited cell colony formation and migration, and induced DNA damage[5]. KAN0438757 (0-5μM) was treated with rat nucleus pulposus primary cells (NPP) for 24-72 h, which reduced tumor necrosis factor-α (TNF-α)-induced extracellular matrix (ECM) degradation, regulated the abnormal glycolytic energy metabolism phenotype, and had no cytotoxicity [6].
In vivo, KAN0438757 (25mg/kg) was treated by intraperitoneal injection in two pancreatitis model mice, and decreased levels of amylase and apoptosis activity were observed in both mice, inhibiting the exacerbation of fatty acid ethyl ester-induced severe acute pancreatitis (FAEE-SAP) and caerulein-induced acute pancreatitis (CAE-AP) [7].
References:
[1]Gustafsson N M S, Färnegårdh K, Bonagas N, et al. Targeting PFKFB3 radiosensitizes cancer cells and suppresses homologous recombination[J]. Nature communications, 2018, 9(1): 3872.
[2]Jones B C, Pohlmann P R, Clarke R, et al. Treatment against glucose-dependent cancers through metabolic PFKFB3 targeting of glycolytic flux[J]. Cancer and Metastasis Reviews, 2022, 41(2): 447-458.
[3]Wang S, Bei Y, Tian Q, et al. PFKFB4 facilitates palbociclib resistance in oestrogen receptor‐positive breast cancer by enhancing stemness[J]. Cell Proliferation, 2023, 56(1): e13337.
[4]De Oliveira T, Goldhardt T, Edelmann M, et al. Effects of the novel PFKFB3 inhibitor KAN0438757 on colorectal cancer cells and its systemic toxicity evaluation in vivo[J]. Cancers, 2021, 13(5): 1011.
[5]Özdemir D, Saruhan S, Ağca C A. KAN0438757: a novel PFKFB3 inhibitor that induces programmed cell death and suppresses cell migration in non-small cell lung carcinoma cells[J]. 2023.
[6]Cao X, Wang X, Rong K, et al. Specific PFKFB3 inhibitor memorably ameliorates intervertebral disc degeneration via inhibiting NF-κB and MAPK signaling pathway and reprogramming of energy metabolism of nucleus pulposus cells[J]. Oxidative Medicine and Cellular Longevity, 2022.
[7]Ergashev A, Shi F, Liu Z, et al. KAN0438757, a novel PFKFB3 inhibitor, prevent the progression of severe acute pancreatitis via the Nrf2/HO-1 pathway in infiltrated macrophage[J]. Free Radical Biology and Medicine, 2024, 210: 130-145.
KAN0438757是一种有效的选择性代谢激酶PFKFB3抑制剂，IC50值为0.19 μM[1]。PFKFB3是一种在糖酵解中发挥关键作用的酶，并在多种癌细胞中过度表达[2]。KAN0438757也可以作为PFKFB4的选择性抑制剂[3]。
在体外，KAN0438757（10-100μM）处理HCT-116、HT-29、HUVECs和正常结肠上皮细胞48 h，剂量依赖性地增加了细胞死亡率，但对正常结肠上皮细胞的影响较小[4]。KAN0438757（1-100μM）处理非小细胞肺癌A549细胞24-72h，显著降低了细胞活力，抑制了细胞的集落形成、迁移，诱导了DNA损伤[5]。KAN0438757（0-5μM）处理大鼠髓核原代细胞（NPP）24-72h，减轻了肿瘤坏死因子-α（TNF-α）诱导的细胞外基质（ECM）降解，调节了糖酵解能量代谢表型的异常，且没有细胞毒性[6]。
在体内，KAN0438757（25 mg/kg）通过腹腔注射治疗两种胰腺炎模型小鼠，均观察到淀粉酶和细胞凋亡活性水平下降，抑制了脂肪酸乙酯诱导的重症急性胰腺炎（FAEE-SAP）和雨蛙素诱导的急性胰腺炎（CAE-AP）的恶化[7]。
| Cas No. | 1451255-59-6 | SDF | |
| Canonical SMILES | O=C(OCCO)C1=CC=C(NS(=O)(C2=CC(C3=CC(F)=CC=C3O)=CC=C2)=O)C=C1O | ||
| 分子式 | C21H18FNO7S | 分子量 | 447.43 |
| 溶解度 | DMSO: 130 mg/mL (290.55 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 | 2.235 mL | 11.1749 mL | 22.3499 mL |
| 5 mM | 0.447 mL | 2.235 mL | 4.47 mL |
| 10 mM | 0.2235 mL | 1.1175 mL | 2.235 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 | ||||||||||
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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。
Effects of the Novel PFKFB3 Inhibitor KAN0438757 on Colorectal Cancer Cells and Its Systemic Toxicity Evaluation In Vivo
Cancers (Basel) 2021 Feb 28;13(5):1011.PMID:33671096DOI:10.3390/cancers13051011.
Background: Despite substantial progress made in the last decades in colorectal cancer (CRC) research, new treatment approaches are still needed to improve patients' long-term survival. To date, the promising strategy to target tumor angiogenesis metabolically together with a sensitization of CRC to chemo- and/or radiotherapy by PFKFB3 (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-3) inhibition has never been tested. Therefore, initial evaluation and validation of newly developed compounds such as KAN0438757 and their effects on CRC cells are crucial steps preceding to in vivo preclinical studies, which in turn may consolidate new therapeutic targets. Materials and methods: The efficiency of KAN0438757 to block PFKFB3 expression and translation in human CRC cells was evaluated by immunoblotting and real-time PCR. Functional in vitro assays assessed the effects of KAN0438757 on cell viability, proliferation, survival, adhesion, migration and invasion. Additionally, we evaluated the effects of KAN0438757 on matched patient-derived normal and tumor organoids and its systemic toxicity in vivo in C57BL6/N mice. Results: High PFKFB3 expression is correlated with a worse survival in CRC patients. KAN0438757 reduces PFKFB3 protein expression without affecting its transcriptional regulation. Additionally, a concentration-dependent anti-proliferative effect was observed. The migration and invasion capacity of cancer cells were significantly reduced, independent of the anti-proliferative effect. When treating colonic patient-derived organoids with KAN0438757 an impressive effect on tumor organoids growth was apparent, surprisingly sparing normal colonic organoids. No high-grade toxicity was observed in vivo. Conclusion: The PFKFB3 inhibitor KAN0438757 significantly reduced CRC cell migration, invasion and survival. Moreover, on patient-derived cancer organoids KAN0438757 showed significant effects on growth, without being overly toxic in normal colon organoids and healthy mice. Our findings strongly encourage further translational studies to evaluate KAN0438757 in CRC therapy.
Targeting PFKFB3 radiosensitizes cancer cells and suppresses homologous recombination
Nat Commun 2018 Sep 24;9(1):3872.PMID:30250201DOI:10.1038/s41467-018-06287-x.
The glycolytic PFKFB3 enzyme is widely overexpressed in cancer cells and an emerging anti-cancer target. Here, we identify PFKFB3 as a critical factor in homologous recombination (HR) repair of DNA double-strand breaks. PFKFB3 rapidly relocates into ionizing radiation (IR)-induced nuclear foci in an MRN-ATM-γH2AX-MDC1-dependent manner and co-localizes with DNA damage and HR repair proteins. PFKFB3 relocalization is critical for recruitment of HR proteins, HR activity, and cell survival upon IR. We develop KAN0438757, a small molecule inhibitor that potently targets PFKFB3. Pharmacological PFKFB3 inhibition impairs recruitment of ribonucleotide reductase M2 and deoxynucleotide incorporation upon DNA repair, and reduces dNTP levels. Importantly, KAN0438757 induces radiosensitization in transformed cells while leaving non-transformed cells unaffected. In summary, we identify a key role for PFKFB3 enzymatic activity in HR repair and present KAN0438757, a selective PFKFB3 inhibitor that could potentially be used as a strategy for the treatment of cancer.
Specific PFKFB3 Inhibitor Memorably Ameliorates Intervertebral Disc Degeneration via Inhibiting NF- κ B and MAPK Signaling Pathway and Reprogramming of Energy Metabolism of Nucleus Pulposus Cells
Oxid Med Cell Longev 2022 Sep 21;2022:7548145.PMID:36187335DOI:10.1155/2022/7548145.
Intervertebral disc (IVD) degeneration (IVDD) is a characteristic of the dominating pathological processes of nucleus pulposus (NP) cell senescence, abnormal synthesis and irregular distribution of extracellular matrix (ECM), and tumor necrosis factor-α (TNF-α) induced inflammation. Nowadays, IVD acid environment variation which accelerates the pathological processes mentioned above arouses researchers' attention. KAN0438757 (KAN) is an effective inhibitor of selective metabolic kinase phosphofructokinase-2/fructose-2,6-bisphosphatase 3 (PFKFB3) that has both energy metabolism reprogramming and anti-inflammatory effects. Therefore, a potential therapeutic benefit of KAN lies in its ability to inhibit the development of IVDD. This study examined in vitro KAN toxicity in NP primary cells (NPPs). Moreover, KAN influenced tumor necrosis factor-α (TNF-α) induced ECM anabolism and catabolism; the inflammatory signaling pathway activation and the energy metabolism phenotype were also examined in NPPs. Furthermore, KAN's therapeutic effect was investigated in vivo using the rat tail disc puncture model. Phenotypically speaking, the KAN treatment partially rescued the ECM degradation and glycolysis energy metabolism phenotypes of NPPs induced by TNF-α. In terms of mechanism, KAN inhibited the activation of MAPK and NF-κB inflammatory signaling pathways induced by TNF-α and reprogramed the energy metabolism. For the therapeutic aspect, the rat tail disc puncture model demonstrated that KAN has a significant ameliorated effect on the progression of IVDD. To sum up, our research successfully authenticated the potential therapeutic effect of KAN on IVDD and declaimed its mechanisms of both novel energy metabolism reprogramming and conventional anti-inflammation effect.