STO-609 is a selective and cell-permeable inhibitor of the Ca2+/calmodulin-dependent protein kinase kinase (CaM-KK), with Ki values of 80 and 15ng/mL for recombinant CaM-KKα and CaM-KKβ, respectively[1]. CaM-KK is a key signal transduction protein that plays an important role in intracellular calcium signal transduction by activating members of the CaM kinase family (such as CaM-KI, CaM-KIV, etc.)[2]. STO-609 is typically used to study CAM-KK-related signaling pathways and their roles in various cellular physiological processes such as cell proliferation, differentiation, metabolism, and neural signal transduction[3][4].
In vitro, treatment of non-functional pituitary adenoma (NFPA) cells with STO-609 (0.4-51.2μM; 24h)significantly inhibits cells proliferation and migration and induces apoptosis in a dose-dependent manner by suppressing the Ca²⁺/CaM signaling pathway[5]. Treatment of insect neurosecretory cells with STO-609 (15μM; 10min) significantly reduced nicotine-induced currents and intracellular calcium levels increase by inhibiting the CaMKK/AMPK pathway[6].
In vivo, STO-609 (30μg/kg; i.p.; twice a week; 3 weeks) significantly reduced the lung weight of mice inhibited experimental lung metastasis in mice with oral squamous cell carcinoma (OSCC) cells overexpressing EP4[7].
References:
[1] Tokumitsu H, Inuzuka H, Ishikawa Y, Ikeda M, Saji I, Kobayashi R. STO-609, a specific inhibitor of the Ca(2+)/calmodulin-dependent protein kinase kinase. J Biol Chem. 2002;277(18):15813-15818.
[2] Tokumitsu H, Sakagami H. Molecular Mechanisms Underlying Ca2+/Calmodulin-Dependent Protein Kinase Kinase Signal Transduction. Int J Mol Sci. 2022;23(19):11025.
[3] York B, Li F, Lin F, et al. Pharmacological inhibition of CaMKK2 with the selective antagonist STO-609 regresses NAFLD. Sci Rep. 2017;7(1):11793.
[4] Fujiwara Y, Hiraoka Y, Fujimoto T, Kanayama N, Magari M, Tokumitsu H. Analysis of Distinct Roles of CaMKK Isoforms Using STO-609-Resistant Mutants in Living Cells. Biochemistry. 2015;54(25):3969-3977.
[5] Wu B, Jiang S, Wang X, et al. Identification of driver genes and key pathways of non-functional pituitary adenomas predicts the therapeutic effect of STO-609. PLoS One. 2020;15(10):e0240230.
[6] Taha M, Houchat JN, Taillebois E, Thany SH. The calcium-calmodulin-dependent protein kinase kinase inhibitor, STO-609, inhibits nicotine-induced currents and intracellular calcium increase in insect neurosecretory cells. J Neurochem. 2024;168(7):1281-1296.
[7] Ishikawa S, Umemura M, Nakakaji R, et al. EP4-induced mitochondrial localization and cell migration mediated by CALML6 in human oral squamous cell carcinoma. Commun Biol. 2024;7(1):567.
STO-609是一种选择性且细胞可渗透的Ca²⁺/钙调蛋白依赖性蛋白激酶激酶（CaM-KK）抑制剂，对重组CaM-KKα和CaM-KKβ的Ki值分别为80ng/mL和15ng/mL[1]。CaM-KK是一种关键的信号转导蛋白，通过激活CaM激酶家族成员（如CaM-KI、CaM-KIV等）在细胞内钙信号传导中发挥重要作用[2]。STO-609通常用于研究CaM-KK相关的信号通路及其在细胞增殖、分化、代谢和神经信号传导等多种细胞生理过程中的作用[3][4]。
在体外，STO-609（0.4-51.2μM；处理24小时）通过抑制Ca2+/CaM信号通路, 剂量依赖性地显著抑制非功能性垂体腺瘤（NFPA）细胞的增殖和迁移，并诱导细胞凋亡[5]。在昆虫的神经分泌细胞中，STO-609（15μM；处理10分钟）通过抑制CaMKK/AMPK通路显著降低了尼古丁诱导的电流和细胞内钙水平的升高[6]。
在体内，STO-609（30μg/kg；腹腔注射；每周两次；持续3周）显著降低了过表达EP4的口腔鳞状细胞癌（OSCC）细胞诱导的小鼠的肺重量，并抑制了小鼠实验性肺转移[7]。