CHIR-98014
目录号 : GC12176
CHIR-98014是一种具细胞渗透性的GSK-3α和GSK-3β的强效抑制剂,IC50值分别为0.65nM和0.58nM。
Cas No.:252935-94-7
Sample solution is provided at 25 µL, 10mM.
CHIR-98014 is a potent, cell-permeable inhibitor of GSK-3α and GSK-3β with IC50 values of 0.65nM and 0.58nM, respectively[1]. GSK-3 (glycogen synthase kinase 3) is a serine/threonine protein kinase and plays a key role in many central intracellular signaling pathways, including cell proliferation, migration, inflammation and immune response, glucose regulation, and apoptosis[2, 3]. CHIR-98014 can regulate the Wnt/β-catenin signaling pathway and has a wide range of applications in stem cell maintenance, metabolic diseases, and neurodegenerative disease research[4].
In vitro, pretreatment of cortical and hippocampal neurons with CHIR-98014 (10μM) for 1h significantly reduced PrP1-30-induced neurite loss and significantly reduced the number of dead cells[5]. Treatment of A549 cells with CHIR-98014 (0.25-2μM) for 48h inhibited phosphorylation of Ser46 and Ser392 (p53 activation markers) induced by actinomycin D and Nutlin-3a (A+N), but made the cells sensitive to A+N-induced apoptosis[6].
In vivo, oral treatment of HepG2 liver cancer cell xenograft mice with CHIR-98014 (10mg/kg) for 15 days significantly inhibited tumor growth in mice, and combined with Hjp-6-171, it exerted a synergistic effect[7]. Oral treatment of NSG mice with KMT2A rearranged leukemia with CHIR-98014 (15mg/kg) partially inhibited the tumor burden of mice and significantly prolonged the survival of mice[8].
References:
[1] Ring D B, Johnson K W, Henriksen E J, et al. Selective glycogen synthase kinase 3 inhibitors potentiate insulin activation of glucose transport and utilization in vitro and in vivo[J]. Diabetes, 2003, 52(3): 588-595.
[2] Pan W A, Tsai H Y, Wang S C, et al. The RNA recognition motif of NIFK is required for rRNA maturation during cell cycle progression[J]. RNA biology, 2015, 12(3): 255-267.
[3] Jope R S, Yuskaitis C J, Beurel E. Glycogen synthase kinase-3 (GSK3): inflammation, diseases, and therapeutics[J]. Neurochemical research, 2007, 32: 577-595.
[4] Phukan S, Babu V S, Kannoji A, et al. GSK3β: role in therapeutic landscape and development of modulators[J]. British journal of pharmacology, 2010, 160(1): 1-19.
[5] Zajkowski T, Nieznanska H, Nieznanski K. Stabilization of microtubular cytoskeleton protects neurons from toxicity of N-terminal fragment of cytosolic prion protein[J]. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research, 2015, 1853(10): 2228-2239.
[6] Łasut-Szyszka B, Małachowska B, Gdowicz-Kłosok A, et al. Transcriptome Analysis of Cells exposed to actinomycin D and Nutlin-3a reveals new candidate p53-Target genes and indicates that CHIR-98014 is an important inhibitor of p53 activity[J]. International Journal of Molecular Sciences, 2021, 22(20): 11072.
[7] Liu Y, Xue M, Cao D, et al. Multi-omics characterization of WNT pathway reactivation to ameliorate BET inhibitor resistance in liver cancer cells[J]. Genomics, 2021, 113(3): 1057-1069.
[8] Wright S, Hu J, Wang H, et al. Interrogating bromodomain inhibitor resistance in KMT2A-rearranged leukemia through combinatorial CRISPR screens[J]. Proceedings of the National Academy of Sciences, 2023, 120(16): e2220134120.
CHIR-98014是一种具细胞渗透性的GSK-3α和GSK-3β的强效抑制剂,IC50值分别为0.65nM和0.58nM[1]。GSK-3(糖原合成酶激酶3)是丝氨酸/苏氨酸蛋白激酶,并且在许多中心细胞内信号传导途径中起关键作用,包括细胞增殖、迁移、炎症和免疫应答、葡萄糖调节和细胞凋亡[2, 3]。CHIR-98014能够调控Wnt/β-catenin信号通路,在干细胞维持、代谢疾病和神经退行性疾病研究中具有广泛应用[4]。
在体外,CHIR-98014(10μM)预处理皮质和海马神经元细胞1h,能够显著减少PrP1-30引起的神经突丢失,并显著减少死细胞的数量[5]。CHIR-98014(0.25-2μM)处理A549细胞48h,抑制了放线菌素D和Nutlin-3a(A+N)诱导的Ser46和Ser392(p53激活标志物)磷酸化,但使细胞对A+N诱导的细胞凋亡敏感[6]。
在体内,CHIR-98014(10mg/kg)通过口服治疗HepG2肝癌细胞异种移植小鼠15天,显著抑制了小鼠体内肿瘤生长,且与Hjp-6-171联合使用可以发挥协同效应[7]。CHIR-98014(15mg/kg)通过口服治疗患有KMT2A重排白血病的NSG小鼠,部分抑制了小鼠的肿瘤负荷,显著延长了小鼠生存期[8]。
Cell experiment [1]: | |
Cell lines | Cortical and hippocampal neurons |
Preparation Method | To stabilize the microtubule cytoskeleton, cells were pretreated with the GSK-3 inhibitor CHIR-98014 (10μM) for 1h and then incubated in the presence or absence of 20μM PrP1-30 for 12h. Confocal microscopy was used to observe cortical and hippocampal neurons. |
Reaction Conditions | 10μM; 1h |
Applications | Treatment of the cortical as well as hippocampal neurons with 10μM CHIR-98014 prevents loss of neurites caused by 20μM PrP1-30. |
Animal experiment [2]: | |
Animal models | Male CB17-SCID mice |
Preparation Method | Male CB17-SCID mice were inoculated with HepG2 cells subcutaneously to establish HepG2 mice subcutaneously transplanted tumor models. Twenty-three days after inoculation, the tumor-bearing mice were divided into 3 groups according to the size of the tumor by the random block method, with 3 mice in each group: CHIR-98014 (10mg/kg) group, Hjp-6-171 (50mg/kg) group and the drug combination group (CHIR-98014 10mg/kg+Hjp-6-171 50mg/kg). Average tumor volume in each group after grouping was about 194mm3. Each group was administered by daily intragastric administration of corresponding inhibitors at a dose of 10mL/kg for 15 days. At the end of the experiment, animals were euthanized with CO2, and subcutaneous tumor tissues were quickly stripped and weighed. |
Dosage form | 10mg/kg; 15 days; p.o. |
Applications | Either treatment with Hjp-6-171 or CHIR-98014 alone could inhibit tumor growth in vivo, combination therapy had a synergistic effect. |
References: |
Cas No. | 252935-94-7 | SDF | |
化学名 | 6-N-[2-[[4-(2,4-dichlorophenyl)-5-imidazol-1-ylpyrimidin-2-yl]amino]ethyl]-3-nitropyridine-2,6-diamine | ||
Canonical SMILES | C1=CC(=C(C=C1Cl)Cl)C2=NC(=NC=C2N3C=CN=C3)NCCNC4=NC(=C(C=C4)[N+](=O)[O-])N | ||
分子式 | C20H17Cl2N9O2 | 分子量 | 486.31 |
溶解度 | ≥ 8.1mg/mL in DMSO with gentle warming | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg |
1 mM | 2.0563 mL | 10.2815 mL | 20.563 mL |
5 mM | 0.4113 mL | 2.0563 mL | 4.1126 mL |
10 mM | 0.2056 mL | 1.0282 mL | 2.0563 mL |
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