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]。