GSK621

GSK621 is a specific AMP-activated protein kinase (AMPK) agonist. GSK621 can induce autophagy and apoptosis by activating the AMPK signaling pathway^[1-2]. GSK621 exerts selective cytotoxicity independently of mTORC1 activation via the eIF2α signaling pathway. GSK621 can be used in research related to the treatment of various cancers^[3-4].

In vitro, MC3T3-E1 osteoblasts and primary osteoblasts were co-treated with GSK621 (2.5-25μM) and H₂O₂ (250μM) for 24 hours. GSK621 activated the AMPK signaling pathway, increased NADPH content, inhibited reactive oxygen species (ROS) production, and started protective autophagy, thereby alleviating H₂O₂-induced cell death and apoptosis^[5]. Human glioma cells (U87MG and U251MG) were co-treated with GSK621 (10μM) and temozolomide (TMZ; 100μM) for 1-8 days. GSK621 significantly enhanced TMZ-induced cytotoxicity and apoptosis activation but did not produce significant cytotoxicity in primary human astrocytes^[6].

In vivo, GSK621 (25mg/kg) was administered once daily via intraperitoneal injection to SCID mice bearing A375 melanoma xenograft models for 15 days. GSK621 significantly inhibited the growth of A375 tumors, and GSK621 anti-tumor activity was further enhanced when combined with the MEK-ERK inhibitor MEK162 (5mg/kg; oral gavage)^[7]. In BALB/c mice with endotoxic shock induced by intraperitoneal injection of LPS (30mg/kg) and D-galactosamine (300mg/kg), a single oral gavage of GSK621 (50mg/kg) significantly suppressed LPS-induced serum TNFα production and increased the survival rate of mice within 48 hours, protecting rate from endotoxic shock^[8].

References:
[1] Li Y, Xiao G, Fu X, et al. CH25H/25-HC promotes pulmonary fibrosis via AMPK/STAT6 pathway-dependent M2 macrophage polarization in COPD. Immunobiology. 2025 May;230(3):152908.
[2] Grenier A, Poulain L, Mondesir J, et al. AMPK-PERK axis represses oxidative metabolism and enhances apoptotic priming of mitochondria in acute myeloid leukemia. Cell Rep. 2022 Jan 4;38(1):110197.
[3] Mondesir J, Ghisi M, Poillet L, et al. AMPK activation induces immunogenic cell death in AML. Blood Adv. 2023 Dec 26;7(24):7585-7596.
[4] Wang X, Li G, Liu J, et al. GSK621 ameliorates lipid accumulation via AMPK pathways and reduces oxidative stress in hepatocytes in vitro and in obese mice in vivo. Life Sci. 2025 Aug 1;374:123687.
[5] Liu W, Mao L, Ji F, et al. Targeted activation of AMPK by GSK621 ameliorates H2O2-induced damages in osteoblasts. Oncotarget. 2017 Feb 7;8(6):10543-10552.
[6] Jiang H, Liu W, Zhan SK, et al. GSK621 Targets Glioma Cells via Activating AMP-Activated Protein Kinase Signalings. PLoS One. 2016 Aug 17;11(8):e0161017.
[7] Chen L, Chen Q, Deng G, et al. AMPK activation by GSK621 inhibits human melanoma cells in vitro and in vivo. Biochem Biophys Res Commun. 2016 Nov 25;480(4):515-521.
[8] Wu YH, Li Q, Li P, et al. GSK621 activates AMPK signaling to inhibit LPS-induced TNFα production. Biochem Biophys Res Commun. 2016 Nov 18;480(3):289-295.

GSK621是一种特异性的AMP活化蛋白激酶（AMPK）激动剂。GSK621可通过激活AMPK信号通路来诱导自噬和细胞凋亡^[1-2]。GSK621通过eIF2α信号通路独立于mTORC1激活来发挥选择性细胞毒性作用。GSK621可用于多种癌症治疗的相关研究^[3-4]。

在体外，GSK621（2.5-25μM）与H₂O₂（250μM）共处理MC3T3-E1成骨细胞及原代成骨细胞24小时。GSK621通过激活AMPK信号通路，增加NADPH含量抑制活性氧（ROS）产生，并启动保护性自噬，以减轻H₂O₂诱导的细胞死亡和凋亡^[5]。GSK621（10μM）与temozolomide（TMZ；100μM）共处理人类胶质瘤细胞（U87MG和U251MG）1-8天。GSK621显著增强TMZ诱导的细胞毒性和凋亡激活，但对原代人类星形胶质细胞不产生明显的细胞毒性^[6]。

在体内，GSK621（25mg/kg）每天一次腹腔注射于A375黑色素瘤异种移植模型的SCID小鼠，持续15天。GSK621显著抑制了A375肿瘤的生长，并且与MEK-ERK抑制剂MEK162（5mg/kg；口服灌胃）联用可进一步增强GSK621的抗肿瘤活性^[7]。GSK621（50mg/kg）通过口服灌胃，单次处理经LPS（30mg/kg）和D-半乳糖胺（300mg/kg）腹腔注射诱导内毒素休克的BALB/c小鼠。GSK621显著抑制了LPS诱导的血清TNFα产生，并提高了小鼠在48小时内的生存率，保护小鼠免受内毒素休克^[8]。