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]。