SPD304是一种选择性的肿瘤坏死因子α（TNF-α）抑制剂，IC50值为22μM。
Cas No.:1049741-03-8
Sample solution is provided at 25 µL, 10mM.
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SPD304 is a selective inhibitor of tumor necrosis factor α (TNF-α), with an IC50 value of 22μM[1]. SPD304 promotes dissociation of TNF trimers and therefore blocks the interaction of TNF and the related receptor [2]. SPD304 has been widely used to block the TNF-α/NF-κB/CUL4B pathway to induce cell cycle arrest in S phase [3].
In vitro, SPD304 treatment at 30µM for 24h significantly induced HEK293T cell death[4]. Treatment with 25µM SPD304 for 24h significantly inhibited TNFα activity and reduced L929 cell viability[5]. Treatment of GH3 cells with 8µM SPD304 for 48h inhibited TNFα-induced upregulation of MAPK pathway proteins and inhibited cell proliferation, migration, and invasion[6]. Preincubation with 1µM SPD304 for 24 hours significantly inhibited IL-8 and IL-6 levels in human dermal fibroblasts (HDFs)[7].
In vivo, SPD304 treatment (5µg; dissolved in 10µl artificial cerebrospinal fluid containing 5% DMSO) via intracerebroventricular injection for 5min inhibited the increase in blood pressure, heart rate, and renal sympathetic activity induced by TACE (TNF-α–converting enzyme) in heart failure rats[8].
References:
[1] He M M, Smith A S, Oslob J D, et al. Small-molecule inhibition of TNF-α[J]. Science, 2005, 310(5750): 1022-1025.
[2] Alexiou P, Papakyriakou A, Ntougkos E, et al. Rationally designed less toxic SPD‐304 analogs and preliminary evaluation of their TNF inhibitory effects[J]. Archiv der Pharmazie, 2014, 347(11): 798-805.
[3] Zhang C, Chen B, Jiang K, et al. Activation of TNF‐α/NF‐κB axis enhances CRL 4 BDCAF 11 E3 ligase activity and regulates cell cycle progression in human osteosarcoma cells[J]. Molecular oncology, 2018, 12(4): 476-494.
[4] Shen Q, Zhang C, Liu H, et al. De novo design of helical peptides to inhibit tumor necrosis factor-α by disrupting its trimer formation[J]. MedChemComm, 2016, 7(4): 725-729.
[5] Mascret A, Mouhsine H, Attia G, et al. New contributions to the drug profile of TNFα inhibitor SPD304: Affinity, selectivity and ADMET considerations[J]. European Journal of Pharmacology, 2021, 907: 174285.
[6] Wu X, Gong L, Li B, et al. TNF‐α can promote membrane invasion by activating the MAPK/MMP9 signaling pathway through autocrine in bone‐invasive pituitary adenoma[J]. CNS Neuroscience & Therapeutics, 2024, 30(5): e14749.
[7] Javaid N, Patra M C, Cho D E, et al. An orally active, small-molecule TNF inhibitor that disrupts the homotrimerization interface improves inflammatory arthritis in mice[J]. Science Signaling, 2022, 15(759): eabi8713.
[8] Yu Y, Cao Y, Bell B, et al. Brain TACE (tumor necrosis factor-α–converting enzyme) contributes to sympathetic excitation in heart failure rats[J]. Hypertension, 2019, 74(1): 63-72.
SPD304是一种选择性的肿瘤坏死因子α（TNF-α）抑制剂，IC50值为22μM[1]。SPD304可促进TNF三聚体的解离，从而阻断TNF与相关受体的相互作用[2]。SPD304已被广泛用于阻断TNF-α/NF-κB/CUL4B通路，以诱导细胞周期阻滞于S期[3]。
在体外，使用30μM的SPD304处理HEK293T细胞24小时，能显著诱导细胞死亡[4]。使用25μM的SPD304处理24小时，能显著抑制TNFα活性并降低L929细胞活力[5]。用8μM的SPD304处理GH3细胞48小时，可抑制TNFα诱导的MAPK通路蛋白上调，并抑制细胞增殖、迁移和侵袭[6]。用1μM的SPD304预孵育人真皮成纤维细胞（HDFs）24小时，能显著抑制IL-8和IL-6的水平[7]。
在体内，通过脑室内注射SPD304（5μg；溶于含5%DMSO的10μl人工脑脊液）5分钟，可抑制心力衰竭大鼠中TACE(TNF-α-converting enzyme)诱导的血压、心率和肾交感神经活性的升高[6]。
| Cell experiment [1]: | |
Cell lines | HEK293T cells |
Preparation Method | HEK293T cells were plated in 96-well plates at 1×104 cells per well and cultured in 100μl of DMEM at 37°C for 24 hours. Then, to each well was added 50μl of SPD304 at various concentrations (1, 10, 20, 40, 60, 80, and 100µM). In the control groups, 50μl of DMEM was used. Wells containing only media without cells and additives were used as blanks. Cell viability was measured after 24 hours. |
Reaction Conditions | 1, 10, 20, 40, 60, 80, and 100µM; 24h |
Applications | SPD304 treatment significantly the cell viability of HEK293T cells in a dose-dependent manner. |
| Animal experiment [2]: | |
Animal models | Male Sprague-Dawley rats |
Preparation Method | Male Sprague-Dawley rats (225-275g) were housed in temperature (23±2°C) and light-controlled (12:12-hour light-dark cycle) animal care facility. Heart failure (HF) and sham-operated (Sham) rats were produced by coronary artery ligation or sham surgery. Sham (n=6) and HF (n=6) rats were treated with intracerebroventricular injection of TACE (300ng in 3µl artificial cerebrospinal fluid over 1 minute) immediately after intracerebroventricular pretreatment with the SPD304 (5µg in 10µl 5% DMSO in artificial cerebrospinal fluid over 5 minutes). Mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA) were analyzed. |
Dosage form | 5µg for once; i.c.v. |
Applications | SPD304 treatment inhibited the increase in blood pressure, HR, and RSNA induced by TACE in HF rats. |
References: | |
| Cas No. | 1049741-03-8 | SDF | Download SDF |
| 分子式 | C32H34Cl2F3N3O2 | 分子量 | 620.53 |
| 溶解度 | DMSO : 11.36 mg/mL (18.31 mM; ultrasonic and warming and heat to 60°C) | 储存条件 | 4°C, away from moisture |
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| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.6115 mL | 8.0576 mL | 16.1153 mL |
| 5 mM | 322.3 μL | 1.6115 mL | 3.2231 mL |
| 10 mM | 161.2 μL | 805.8 μL | 1.6115 mL |
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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 | ||||||||||
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工作液浓度： mg/ml；
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2.
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