GSK690693是一种ATP竞争性的泛Akt（pan-Akt）激酶抑制剂，通过特异性阻断Akt信号轴发挥调控作用。GSK690693在胰腺癌来源异种移植（PDX）小鼠模型中，可使肿瘤体积减少至盐水对照组的61%，并通过干扰Akt通路实现衰老-凋亡信号的转换，显著改善耐药性[1]。GSK690693在结肠癌的研究中，与Irinotecan (CPT-11)联用可降低EVI1高表达细胞系的存活率，抑制肿瘤进展[2]，相关实验采用2D/3D细胞模型（如HCT116等结肠癌细胞系）和异种移植小鼠模型[2]。

在神经系统研究中，GSK690693（CAS No.：937174-76-0）表现出多重活性：在创伤后应激障碍（PTSD）小鼠模型（C57BL/6品系）中，GSK690693能阻断跑步机运动对海马神经发生和行为改善的促进作用[3]。而在大鼠原代神经元培养体系中，GSK690693能完全消除CXCL12诱导的胆碱能基因（CHT1、VAChT、ChAT）表达上调，并逆转胆碱乙酰转移酶活性和乙酰胆碱产量的增加[4]。GSK690693在骨癌痛模型（BCP，SD大鼠）中，通过抑制脊髓组织Akt蛋白磷酸化，降低WNK1表达，从而发挥缓解作用[5]。GSK690693（AbMole，M1789）在细胞凋亡调控中表现出多机制特性。

首先在横纹肌肉瘤（RMS）细胞中，GSK690693与组蛋白去乙酰化酶抑制剂JNJ-26481585（Quisinostat）协同增强caspase-9/-3的活化，该效应可被BCL-2或MCL-1过表达所拮抗[6]。GSK690693在卵巢癌细胞系OVCAR3中，联合miR-1284过表达可下调p-Akt和Bcl-2，同时上调Bax和caspase-3表达[7]。此外，在骨肉瘤143B细胞系及小鼠异种移植模型中，GSK690693通过抑制ZIP10-ITGA10-PI3K/AKT轴逆转化疗耐药性[8]。在干细胞分化调控方面，GSK690693可阻断STC2诱导的室管膜下区神经前体细胞（NSPCs，来源于小鼠）的神经元分化，而Akt激活剂SC79能逆转此效应[9]。

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参考文献及鸣谢

[1] Yang, D.; Zhang, Q.; Ma, Y.; et al. Augmenting the therapeutic efficacy of adenosine against pancreatic cancer by switching the Akt/p21-dependent senescence to apoptosis. EBioMedicine 2019, 47, 114-127.

[2] Pradeepa; Suresh, V.; Senapati, S.; et al. AKT inhibition sensitizes EVI1 expressing colon cancer cells to irinotecan therapy by regulating the Akt/mTOR axis. Cellular oncology (Dordrecht, Netherlands) 2022, 45 (4), 659-675.

[3] Sun, L.; Cui, K.; Xing, F.; et al. Akt dependent adult hippocampal neurogenesis regulates the behavioral improvement of treadmill running to mice model of post-traumatic stress disorder. Behavioural brain research 2020, 379, 112375.

[4] Yan, J.; Zhao, W.; Guo, M.; et al. CXCL12 Regulates the Cholinergic Locus and CHT1 Through Akt Signaling Pathway. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 2016, 40 (5), 982-992.

[5] Fu, X.; Zhang, Y.; Zhang, R. Regulatory role of PI3K/Akt/WNK1 signal pathway in mouse model of bone cancer pain. Scientific reports 2023, 13 (1), 14321.

[6] Haydn, T.; Metzger, E.; Schuele, R.; et al. Concomitant epigenetic targeting of LSD1 and HDAC synergistically induces mitochondrial apoptosis in rhabdomyosarcoma cells. Cell death & disease 2017, 8 (6), e2879.

[7] Pan, C.; Wang, D.; Zhang, Y.; et al. MicroRNA-1284 Inhibits Cell Viability and Induces Apoptosis of Ovarian Cancer Cell Line OVCAR3. Oncology research 2016, 24 (6), 429-435.

[8] Li, H.; Shen, X.; Ma, M.; et al. ZIP10 drives osteosarcoma proliferation and chemoresistance through ITGA10-mediated activation of the PI3K/AKT pathway. Journal of experimental & clinical cancer research : CR 2021, 40 (1), 340.

[9] Guo, Z.; Zhang, H.; Jingele, X.; et al. Stanniocalcin 2 Promotes Neuronal Differentiation in Neural Stem/Progenitor Cells of the Mouse Subventricular Zone Through Activation of AKT Pathway. Stem cells and development 2024, 33 (19-20), 551-561.