GCN2-IN-1 (A-92) is a potent and selective inhibitor of General Control Nonderepressible 2 kinase (GCN2)[1]. By inhibiting the activity of GCN2 kinase, GCN2-IN-1 affects the phosphorylation of its downstream eukaryotic translation initiation factor eIF2α, thereby modulating the Integrated Stress Response (ISR) signaling pathway[2]. GCN2-IN-1 shows potential as a chemotherapeutic agent for cancer treatment, with mechanisms of action related to the regulation of the cell cycle and stress responses[3-4].
In vitro, treatment of APC-deficient colorectal cancer cells (SW480) with GCN2-IN-1 (3μM) for 6 hours significantly reduced the phosphorylation level of eukaryotic translation initiation factor 2α (eIF2α) and induced apoptosis[5]. Pre-treatment of U2OS cells with GCN2-IN-1 (4μM) for 3 hours, followed by transfection with in vitro transcribed mRNA (1μg) for 1.5 hours, significantly inhibited the formation of stress granules (SGs) induced by mRNA transfection[6]. Treatment of HeLa cells with GCN2-IN-1 (0.63-5μM) for 5 hours significantly inhibited the activity of its target GCN2 and reduced basal eIF2α phosphorylation levels, while increasing protein synthesis[7]. Pre-treatment of U2OS cells with GCN2-IN-1 (4μM) for 3 hours, followed by stimulation with VRB (75μM) for 1 hour, significantly enhanced the formation of stress granules (SGs) and altered granule dynamics[8].
References:
[1] Chen C, Xie Y, Qian S, et al. Multifaceted role of GCN2 in tumor adaptation and therapeutic targeting. Transl Oncol. 2024 Nov;49:102096.
[2] Ghosh JC, Perego M, Agarwal E, et al. Ghost mitochondria drive metastasis through adaptive GCN2/Akt therapeutic vulnerability. Proc Natl Acad Sci U S A. 2022 Feb 22;119(8):e2115624119.
[3] Skrott Z, Mistrik M, Andersen KK, et al. Alcohol-abuse drug disulfiram targets cancer via p97 segregase adaptor NPL4. Nature. 2017 Dec 14;552(7684):194-199.
[4] Gold LT, Masson GR. GCN2: roles in tumour development and progression. Biochem Soc Trans. 2022 Apr 29;50(2):737-745.
[5] Angel M, Fleshler E, Atrash MK, et al. Nuclear RNA-related processes modulate the assembly of cytoplasmic RNA granules. Nucleic Acids Res. 2024 May 22;52(9):5356-5375.
[6] Szaruga M, Janssen DA, de Miguel C, et al. Activation of the integrated stress response by inhibitors of its kinases. Nat Commun. 2023 Sep 8;14(1):5535.
[7] Schmidt S, Gay D, Uthe FW, et al. A MYC-GCN2-eIF2α negative feedback loop limits protein synthesis to prevent MYC-dependent apoptosis in colorectal cancer. Nat Cell Biol. 2019 Nov;21(11):1413-1424.
[8] Schwed-Gross A, Hamiel H, Faber GP, et al. Glucocorticoids enhance chemotherapy-driven stress granule assembly and impair granule dynamics, leading to cell death. J Cell Sci. 2022 Jul 15;135(14):jcs259629.
GCN2-IN-1 (A-92)是一种有效且选择性的一般性调控阻遏蛋白激酶2(GCN2)抑制剂[1]。GCN2-IN-1 通过抑制GCN2激酶的活性，影响其下游的真核翻译起始因子eIF2α的磷酸化过程，进而调节综合应激反应(ISR)信号通路[2]。GCN2-IN-1显示出作为化疗药物治疗癌症的潜力，其作用与调节细胞周期、应激反应等机制相关[3-4]。
在体外，GCN2-IN-1（3μM）处理APC缺陷的结直肠癌细胞（SW480）6小时，显著降低了真核翻译起始因子2α（eIF2α）的磷酸化水平，诱导了细胞凋亡[5]。GCN2-IN-1（4μM）预处理U2OS细胞3小时，随后转染体外转录的mRNA（1μg）1.5小时，显著抑制了由mRNA转染诱导的应激颗粒（stress granules, SGs）的形成[6]。GCN2-IN-1（0.63-5μM）处理HeLa细胞5小时，显著抑制了其靶点GCN2的活性并降低了基础eIF2α磷酸化水平，同时使蛋白质合成增加[7]。GCN2-IN-1（4μM）预处理U2OS细胞3小时，随后以VRB（75μM）刺激1小时，显著增强了应激颗粒（stress granules, SGs）的形成并改变了颗粒动力学特性[8]。