UNC 3230
目录号 : GC13054
UNC 3230是一种具有高效选择性的ATP竞争性磷脂酰肌醇 4-磷酸 5-激酶 1C型（PIP5K1C）抑制剂，IC50值为41nM。
Cas No.:1031602-63-7
Sample solution is provided at 25 µL, 10mM.
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UNC 3230 is a highly selective and ATP-competitive phosphatidylinositol 4-phosphate 5-kinase type 1C (PIP5K1C) inhibitor with an IC50 value of 41nM[1,2]. By inhibiting PIP5K1C, UNC 3230 reduces PIP2 levels in dorsal root ganglion (DRG) neurons, leading to decreased calcium signaling and alleviation of pain hypersensitivity[3]. UNC 3230 is commonly used in research to investigate the specific mechanisms of PIP5K1C and its related pathways in pain regulation and tumorigenesis[1,4].
In vitro, treatment of mouse oligodendrocyte FBD-102b cells with UNC 3230 (5μM) for 2 days inhibited cellular morphological differentiation and reduced the expression levels of myelin differentiation marker proteins PLP1 and CNPase[5]. Pretreatment of hACE2-GFP-expressing HEK293T cells with UNC 3230 (0.5μM), followed by co-incubation with the spike protein receptor-binding domain (RBD) for 2h, effectively inhibited ACE2-mediated endocytosis triggered by the spike protein[6]. Treatment of α-Syn-expressing SH-SY5Y cells with UNC 3230 (100nM) for 24h significantly reduced the accumulation of α-Syn near the cell membrane[7].
In vivo, when xenograft tumors formed by SW480 cells in specific pathogen-free female athymic nude mice reached a visible size (approximately 200mm3), administration of UNC 3230 (5mg/kg; three times/week) via intraperitoneal injection for 3 weeks significantly reduced tumor burden, glucose levels, and lactate levels in the subcutaneous model[8]. Intrathecal injection of UNC 3230 (2nM; 5μL) in wild-type mice significantly increased their paw withdrawal latency in response to noxious heat stimuli within 2h post-injection[1].
References:
[1] WRIGHT B D, LOO L, STREET S E, et al. The lipid kinase PIP5K1C regulates pain signaling and sensitization[J]. Neuron, 2014, 82(4): 836-847.
[2] WRIGHT B D, SIMPSON C, STASHKO M, et al. Development of a high-throughput screening assay to identify inhibitors of the lipid kinase PIP5K1C[J]. Journal of Biomolecular Screening, 2015, 20(5): 655-662.
[3] LOO L, WRIGHT B D, ZYLKA M J. Lipid kinases as therapeutic targets for chronic pain[J]. Pain, 2015, 156: S2-S10.
[4] HOFBRUCKER-MACKENZIE S A, SEEMANN E, WESTERMANN M, et al. Long-term depression in neurons involves temporal and ultra-structural dynamics of phosphatidylinositol-4, 5-bisphosphate relying on PIP5K, PTEN and PLC[J]. Communications Biology, 2023, 6(1): 366.
[5] KATO Y, OCHIAI A, SEKI Y, et al. Phospholipase D and phosphatidylinositol-4-phosphate 5-kinase 1 are involved in the regulation of oligodendrocyte morphological differentiation[J]. Experimental Cell Research, 2021, 405(1): 112654.
[6] SEO Y, JANG Y, LEE S G, et al. A dual inhibitor of PIP5K1C and PIKfyve prevents SARS-CoV-2 entry into cells[J]. Experimental & Molecular Medicine, 2024, 56(8): 1736-1749.
[7] HORVATH J D, CASAS M, KUTCHUKIAN C, et al. α-Synuclein-dependent increases in PIP5K1γ drive inositol signaling to promote neurotoxicity[J]. Cell Reports, 2023, 42(10).
[8] PENG W, HUANG W, GE X, et al. Type Iγ phosphatidylinositol phosphate kinase promotes tumor growth by facilitating Warburg effect in colorectal cancer[J]. EBioMedicine, 2019, 44: 375-386.
UNC 3230是一种具有高效选择性的ATP竞争性磷脂酰肌醇 4-磷酸 5-激酶 1C型（PIP5K1C）抑制剂，IC50值为41nM[1,2]。通过抑制PIP5K1C，UNC 3230 降低背根神经节 （DRG） 神经元中 PIP2 的水平，从而导致钙信号传导减少并减轻疼痛超敏反应[3]。UNC 3230通常用于PIP5K1C及相关通路在疼痛调控及肿瘤发生中具体作用机制的研究[1,4]。
在体外，UNC 3230（5μM）处理小鼠少突胶质FBD-102b细胞2天，抑制了细胞的形态分化，并降低了髓鞘分化标记蛋白PLP1和CNPase的表达水平[5]。UNC 3230（0.5μM）预处理表达hACE2-GFP的HEK293T细胞，后与刺突蛋白受体结合域（RBD）共同孵育2h，有效抑制了由刺突蛋白引发的ACE2介导的内吞作用[6]。UNC 3230（100nM）处理可诱导表达α-Syn的SH-SY5Y细胞24h，显著减少了细胞膜附近α-Syn的聚集[7]。
在体内，当无病原体雌性无胸腺裸鼠体内由SW480细胞形成的异种移植瘤生长至可见大小（约200mm3）时，UNC 3230（5mg/kg; three times/week）通过腹腔注射处理小鼠，3周后显著降低了皮下模型中的肿瘤负荷、葡萄糖水平和乳酸水平[8]。UNC 3230（2nM; 5μL）通过鞘内注射处理野生型小鼠，在注射后2h内显著增加了其对伤害性热刺激的缩爪潜伏期[1]。
| Kinase experiment [1]: | |
Preparation Method | Fluorescein-conjugated PI(4)P (1µM) was incubated with 100nM N-terminal His6-tagged full-length (90kDa) recombinant human PIP5K1C and varying concentrations of ATP (threefold serial dilution starting at 1000µM; 11 concentrations total) to determine the ATP Km. The LabChip MSA platform was used to monitor the reactions kinetically (every 5min for ~80min). Michaelis-Menten analysis, using initial rate velocities, revealed an ATP Km of 15µM. Next, reactions containing 1µM PI(4)P, 15µM ATP, and varying concentrations (twofold serial dilution starting at 10nM; seven concentrations total) of PIP5K1C were read kinetically (every 6min for 45min) to determine the concentration of enzyme that would give ~30% conversion of substrate to product at an endpoint within the linear range of the reaction. A final concentration of 3nM PIP5K1C and a 40min incubation time were chosen. Kinase titrations were performed for UNC 3230. Further optimization of the assay (incubation of kinase with UNC 3230 for 20min prior to the addition of kinase), using a new lot of kinase and a tighter dose-response curve (10 point; 1µM highest concentration). |
Reaction Conditions | 20min |
Applications | UNC 3230 was the most potent inhibitors of PIP5K1C (IC50 of 0.120μM). Following assay optimization, UNC 3230 yielded a reproducible potency value of ~40nM. |
| Cell experiment [2]: | |
Cell lines | FBD-102b (Mouse brain oligodendrocyte precursor cell line) |
Preparation Method | FBD-102b cells were allowed to differentiate in the presence of 5μM UNC 3230 for two days. Their cell lysates were used for immunoblotting with an antibody against PLP1, CNPase. Cells with myelin web-like membrane structures bearing multiple processes (primary and secondary branches) from the cell bodies were identified as differentiated. |
Reaction Conditions | 5μM; 2 days |
Applications | Treatment with UNC 3230 blunted morphological differentiation and decreased expression of myelin and differentiation marker proteins (PLP1 and CNPase). |
| Animal experiment [3]: | |
Animal models | Pathogen-free female athymic nude mice implanted with SW480 xenograft tumors |
Preparation Method | Tumor cells (SW480, 1 × 106) were injected subcutaneously into the right scapular region of nude. Mice were intraperitoneally injected with 5mg/kg UNC 3230 three times a week for three weeks when bore visible tumors (200mm3). Lactate production was measured using a commercial Lactate Assay Kit, glucose levels in the culture medium were measured using a Colorimetric Glucose Assay Kit. |
Dosage form | 5mg/kg; three times/week; 3 weeks; i.p. |
Applications | In xenograft tumors formed by SW480 cells, blocking PIPKIγ activity with UNC 3230 significantly reduced tumor burden, glucose level, and lactate level in the subcutaneous model. |
References: | |
| Cas No. | 1031602-63-7 | SDF | |
| 化学名 | 5-(cyclohexanecarboxamido)-2-(phenylamino)thiazole-4-carboxamide | ||
| Canonical SMILES | NC(C1=C(NC(C2CCCCC2)=O)SC(NC3=CC=CC=C3)=N1)=O | ||
| 分子式 | C17H20N4O2S | 分子量 | 344.43 |
| 溶解度 | 0.2mg/mL in ethanol, 30mg/mL in DMSO, or in DMF | 储存条件 | Store at -20°C |
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| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.9033 mL | 14.5167 mL | 29.0335 mL |
| 5 mM | 580.7 μL | 2.9033 mL | 5.8067 mL |
| 10 mM | 290.3 μL | 1.4517 mL | 2.9033 mL |
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