9-ING-41 is a selective and potent GSK-3β inhibitor with an IC50 value of 0.71μM[1]. 9-ING-41 targets NF-κB, thereby leading to the inhibition of downstream NF-κB target moleculars, such as cyclin D1, Bcl-2, anti-apoptotic protein (XIAP), and B-cell lymphoma-extra large (Bcl-XL)[2]. 9-ING-41 has been widely used to regulate cytokine levels and enhance the cytotoxicity of NK cells and T cells against tumor cells[3].
In vitro, 9-ING-41 treatment for 72 hours significantly inhibited the proliferation of VAESBJ cells, G402 cells, and IB112 cells with the IC50 values were 0.2271μM, 0.1741μM, and 0.3210μM, respectively[4]. Treatment with 1μM 9-ING-41 for 3 days significantly induced apoptosis in SUDHL-4 cells and inhibited cell proliferation, accompanied by a significant increase in Caspase 3/7 activity[5]. Treatment with 1μM 9-ING-41 for 24 hours induced cell cycle arrest in T24 cells and decreased the expression of anti-apoptotic molecules Bcl-2 and XIAP[6].
In vivo, three intraperitoneal injections of 9-ING-41 were administered weekly at a dose of 20mg/kg for 4 weeks, which significantly inhibited the tumor growth in the 786-O cell-xenograft mouse model [7]. Continuous intraperitoneal injection of 9-ING-41 (30mg/kg/day) for 7 consecutive days can significantly inhibit the progression of lung fibrosis in mice mediated by TGF-β and bleomycin, and reduce collagen deposition[8].
References:
[1] Gaisina I N, Gallier F, Ougolkov A V, et al. From a natural product lead to the identification of potent and selective benzofuran-3-yl-(indol-3-yl) maleimides as glycogen synthase kinase 3β inhibitors that suppress proliferation and survival of pancreatic cancer cells[J]. Journal of medicinal chemistry, 2009, 52(7): 1853-1863.
[2] Park R, Coveler A L, Cavalcante L, et al. GSK-3β in pancreatic cancer: Spotlight on 9-ING-41, its therapeutic potential and immune modulatory properties[J]. Biology, 2021, 10(7): 610.
[3] Huntington K E, Zhang S, Carneiro B A, et al. GSK3β inhibition by small molecule 9-ING-41 decreases VEGF and other cytokines, and boosts NK and T cell-mediated killing of colorectal tumor cells[J]. Cancer Research, 2021, 81(13_Supplement): 2676-2676.
[4] Verbeke S, Perret R, Chaire V, et al. GSK3-beta as a candidate therapeutic target in soft tissue sarcomas[J]. Journal of Hematology & Oncology, 2021, 14(1): 202.
[5] Karmali R, Chukkapalli V, Gordon L I, et al. GSK-3β inhibitor, 9-ING-41, reduces cell viability and halts proliferation of B-cell lymphoma cell lines as a single agent and in combination with novel agents[J]. Oncotarget, 2017, 8(70): 114924.
[6] Kuroki H, Anraku T, Kazama A, et al. 9-ING-41, a small molecule inhibitor of GSK-3beta, potentiates the effects of anticancer therapeutics in bladder cancer[J]. Scientific reports, 2019, 9(1): 19977.
[7] Pal K, Cao Y, Gaisina I N, et al. Inhibition of GSK-3 induces differentiation and impaired glucose metabolism in renal cancer[J]. Molecular cancer therapeutics, 2014, 13(2): 285-296.
[8] Jeffers A, Qin W, Owens S, et al. Glycogen synthase kinase-3β inhibition with 9-ING-41 attenuates the progression of pulmonary fibrosis[J]. Scientific Reports, 2019, 9(1): 18925.
9-ING-41是一种选择性且强效的GSK-3β抑制剂，IC50值为0.71µM[1]。9-ING-41靶向NF-κB，从而抑制下游NF-κB靶分子，如细胞周期蛋白D1、Bcl-2、抗凋亡蛋白（XIAP）以及B细胞淋巴瘤-特大号（Bcl-XL）[2]。9-ING-41已被广泛用于调节细胞因子水平，并增强NK细胞和T细胞对肿瘤细胞的细胞毒性[3]。
在体外，9-ING-41处理72小时显著抑制了VAESBJ细胞、G402细胞和IB112细胞的增殖，IC50值分别为0.2271µM、0.1741µM和0.3210µM[4]。使用1µM的9-ING-41处理3天，显著诱导了SUDHL-4细胞凋亡并抑制了细胞增殖，同时伴有Caspase 3/7活性的显著增加[5]。使用1µM的9-ING-41处理24小时，诱导了T24细胞的细胞周期阻滞，并降低了抗凋亡分子Bcl-2和XIAP的表达[6]。
在体内，每周腹腔注射9-ING-41三次，剂量为20mg/kg，持续4周，显著抑制了786-O细胞异种移植小鼠模型中的肿瘤生长[7]。连续7天每日腹腔注射9-ING-41（30mg/kg/day），可显著抑制由TGF-β和博来霉素介导的小鼠肺纤维化进展，并减少胶原沉积[8]。