Glutaminase C-IN-1

Glutaminase C-IN-1 is a small molecule that acts as an allosteric inhibitor of glutaminase, which blocks glutaminolysis and influences glutamine metabolism^[1]. Glutaminase C-IN-1 reduces the levels of phospho-S6 ribosomal protein and phospho-AKT (Ser473) and inhibits the AKT/mTOR/S6 signaling pathway^[2]. Glutaminase C-IN-1 is widely used to inhibit the growth of tumor cells, and has been utilized in the development of combined therapies that have effectively eradicated tumors^[3].

In vitro, Glutaminase C-IN-1 treatment for 5 days significantly inhibited the proliferation of HEY, SKOV3 and IGROV-1 cells, with IC₅₀ values of 8.9μM, 29.1μM and 3.5μM, respectively^[4]. Treatment with 10μM Glutaminase C-IN-1 for 3 hours significantly enhanced the activation of Nrf2 in BV2 microglial cells, and increased the expression levels of HO-1 and NQO-1^[5]. Treatment with 20μM Glutaminase C-IN-1 for 48 hours significantly inhibited the glutaminase activity in LM3 cells, resulting in a decrease in the GSH/GSSG ratio within the cells, inducing excessive production of reactive oxygen species (ROS), and causing severe apoptosis ^[6].

In vivo, Glutaminase C-IN-1 treatment via intraperitoneal injection at a dose of 200μg/day for 12 days led to a notable reduction of the tumor size in the P493 cell-xenograft mouse models ^[7]. Three weekly intraperitoneal injections of Glutaminase C-IN-1 (25mg/kg) for 42 days can improve the autoimmune arthritis in SKG mice and reduce the number of Ki-67-positive synovial cells^[8].

References:
[1] Stalnecker C A, Ulrich S M, Li Y, et al. Mechanism by which a recently discovered allosteric inhibitor blocks glutamine metabolism in transformed cells[J]. Proceedings of the National Academy of Sciences, 2015, 112(2): 394-399.
[2] Guo H, Li W, Pan G, et al. The glutaminase inhibitor compound 968 exhibits potent in vitro and in vivo anti-tumor effects in endometrial cancer[J]. Anti-Cancer Agents in Medicinal Chemistry-Anti-Cancer Agents), 2023, 23(2): 210-221.
[3] Kim J H, Lee K J, Seo Y, et al. Effects of metformin on colorectal cancer stem cells depend on alterations in glutamine metabolism[J]. Scientific reports, 2018, 8(1): 409.
[4] Yuan L, Sheng X, Clark L H, et al. Glutaminase inhibitor compound 968 inhibits cell proliferation and sensitizes paclitaxel in ovarian cancer[J]. American journal of translational research, 2016, 8(10): 4265.
[5] Lei W, Kliebe V M, Chen X. An investigation into the impact of a glutaminase inhibitor, compound 968, on Nrf2 signaling[J]. Future Pharmacology, 2021, 1(1): 41-47.
[6] Wang D, Meng G, Zheng M, et al. The glutaminase-1 inhibitor 968 enhances dihydroartemisinin-mediated antitumor efficacy in hepatocellular carcinoma cells[J]. PLoS One, 2016, 11(11): e0166423.
[7] Wang J B, Erickson J W, Fuji R, et al. Targeting mitochondrial glutaminase activity inhibits oncogenic transformation[J]. Cancer cell, 2010, 18(3): 207-219.
[8] Takahashi S, Saegusa J, Sendo S, et al. Glutaminase 1 plays a key role in the cell growth of fibroblast-like synoviocytes in rheumatoid arthritis[J]. Arthritis research & therapy, 2017, 19(1): 76.

Glutaminase C-IN-1是一种小分子，可作为谷氨酰胺酶的变构抑制剂，阻断谷氨酰胺分解并影响谷氨酰胺代谢^[1]。Glutaminase C-IN-1可降低磷酸化S6核糖体蛋白和磷酸化AKT（Ser473）的水平，并抑制AKT/mTOR/S6信号通路^[2]。Glutaminase C-IN-1被广泛用于抑制肿瘤细胞生长，并已用于开发联合疗法，该疗法已有效根除肿瘤^[3]。

在体外，Glutaminase C-IN-1处理5天显著抑制了HEY、SKOV3和IGROV-1细胞的增殖，IC₅₀值分别为8.9µM、29.1µM和3.5µM^[4]。使用10µM的Glutaminase C-IN-1处理BV2小胶质细胞3小时，显著增强了Nrf2的活化，并增加了HO-1和NQO-1的表达水平^[5]。使用20µM的Glutaminase C-IN-1处理LM3细胞48小时，显著抑制了谷氨酰胺酶活性，导致细胞内GSH/GSSG比值下降，诱导活性氧物质（ROS）过量产生，并引起严重凋亡^[6]。

在体内，每日腹腔注射200μg剂量的Glutaminase C-IN-1，持续12天，导致P493细胞异种移植小鼠模型中的肿瘤大小显著减小^[7]。每周三次腹腔注射Glutaminase C-IN-1（25mg/kg），持续42天，可改善SKG小鼠的自身免疫性关节炎，并减少Ki-67阳性滑膜细胞的数量^[8]。