GSK690693 is an ATP-competitive, low nanomolar inhibitor of Akt kinases with IC50 values of 2, 13, and 9 nM for Akt1, 2, and 3, respectively. The apparent Ki for full-length Akt1, 2, and 3 were determined as 1, 4, and 12 nM, respectively.
GSK690693 inhibited the phosphorylation of FKHR/FKHRL1, p70S6K, GSK3α/β, and PRAS40 in BT474 breast tumor cells in a dose-dependent manner [1]. The antiproliferative effect was selective for the malignant cells, as GSK690693 did not inhibit the proliferation of normal human CD4(+) peripheral T lymphocytes as well as mouse thymocytes. Phosphorylation of downstream substrates of AKT was reduced in both sensitive and insensitive cell lines on treatment with GSK690693[2].
GSK690693 was most effective in delaying tumor progression in Lck-MyrAkt2 mice expressing a membrane-bound, constitutively active form of Akt. Both tumors and primary cell cultures displayed downregulation of the Akt pathway, increased apoptosis, and primarily decreased cell proliferation[3].Repeated i.p. administration (once daily for 21 days) produced significant antitumor activity in mice bearing established SKOV-3 ovarian, LNCaP prostate, and BT474 and HCC-1954 breast carcinoma xenografts. Maximal inhibition of 58% to 75% was observed at the end of dosing period with 30 mg/kg/day dose. Daily administration of GSK690693 for 21 days was well-tolerated in mice with [1]. Treatment with antidiabetic agents does not significantly affect GSK690693-induced hyperglycemia in rodents. However, administration of GSK690693 in mice significantly reduces liver glycogen (approximately 90%), suggesting that GSK690693 may inhibit glycogen synthesis and/or activate glycogenolysis[3]. Interrupting treadmill running administrated mice with Akt inhibitor GSK690693 resulted in the blocked the effects of treadmill running to hippocampal neurogenesis and behavioral improvement in PTSD mice model[5]. AKT inhibitor GSK690693 can extend lifespan in Drosophila irrespective of start of the treatment from the beginning of life or the mid-life. Effect of GSK690693 for lifespan extension has been primarily related to the improvements in oxidative resistance, intestinal integrity and increased autophagy, but not in physical activity or starvation resistance[6]. EVI1 knockdown decreased cancer stem cell-like properties and improved irinotecan responses in both cell line and subcutaneous mouse models. Co-treatment with irinotecan and GSK690693 significantly reduced colon cancer cell survival and tumor progression rates[7].
参考文献:
[1]. Rhodes N, Heerding DA, et,al. Characterization of an Akt kinase inhibitor with potent pharmacodynamic and antitumor activity. Cancer Res. 2008 Apr 1;68(7):2366-74. doi: 10.1158/0008-5472.CAN-07-5783. PMID: 18381444.
[2]. Levy DS, Kahana JA, et,al.AKT inhibitor, GSK690693, induces growth inhibition and apoptosis in acute lymphoblastic leukemia cell lines. Blood. 2009 Feb 19;113(8):1723-9. doi: 10.1182/blood-2008-02-137737. Epub 2008 Dec 8. PMID: 19064730.
[3]. Altomare DA, Zhang L, et,al.GSK690693 delays tumor onset and progression in genetically defined mouse models expressing activated Akt. Clin Cancer Res. 2010 Jan 15;16(2):486-96. doi: 10.1158/1078-0432.CCR-09-1026. PMID: 20075391; PMCID: PMC2807995.
[4]. Crouthamel MC, Kahana JA, et,al.Mechanism and management of AKT inhibitor-induced hyperglycemia. Clin Cancer Res. 2009 Jan 1;15(1):217-25. doi: 10.1158/1078-0432.CCR-08-1253. PMID: 19118049.
[5]. Sun L, Cui K, et,al.Akt dependent adult hippocampal neurogenesis regulates the behavioral improvement of treadmill running to mice model of post-traumatic stress disorder. Behav Brain Res. 2020 Feb 3;379:112375. doi: 10.1016/j.bbr.2019.112375. Epub 2019 Nov 20. PMID: 31759046.
[6]. Cheng X, Xie M, et,al.Inhibitor GSK690693 extends Drosophila lifespan via reduce AKT signaling pathway. Mech Ageing Dev. 2022 Mar;202:111633. doi: 10.1016/j.mad.2022.111633. Epub 2022 Jan 20. PMID: 35065134.
[7]. Pradeepa, Suresh V, et,al.AKT inhibition sensitizes EVI1 expressing colon cancer cells to irinotecan therapy by regulating the Akt/mTOR axis. Cell Oncol (Dordr). 2022 Aug;45(4):659-675. doi: 10.1007/s13402-022-00690-9. Epub 2022 Jul 14. PMID: 35834097.
GSK690693 是一种 ATP 竞争性低纳摩尔 Akt 激酶抑制剂，对 Akt1、2 和 3 的 IC50 值分别为 2、13 和 9 nM。全长Akt1、2和3的表观Ki值分别为1、4和12 nM。
GSK690693 以剂量依赖性方式抑制 BT474 乳腺肿瘤细胞中 FKHR/FKHRL1、p70S6K、GSK3α/β 和 PRAS40 的磷酸化[1]。抗增殖作用对恶性细胞具有选择性，因为 GSK690693 不抑制正常人 CD4(+) 外周 T 淋巴细胞和小鼠胸腺细胞的增殖。在 GSK690693[2] 处理后，敏感和不敏感细胞系中 AKT 下游底物的磷酸化均降低。
GSK690693 在延迟 Lck-MyrAkt2 小鼠的肿瘤进展方面最有效，该小鼠表达膜结合的组成型活性 Akt。肿瘤和原代细胞培养物均表现出 Akt 通路下调、细胞凋亡增加和主要是细胞增殖减少[3]。重复 i.p.给药（每天一次，持续 21 天）在携带已建立的 SKOV-3 卵巢、LNCaP 前列腺以及 BT474 和 HCC-1954 乳腺癌异种移植物的小鼠中产生显着的抗肿瘤活性。以 30 mg/kg/天的剂量在给药期结束时观察到 58% 至 75% 的最大抑制。 [1] 小鼠对每天服用 GSK690693 21 天具有良好的耐受性。用抗糖尿病药物治疗不会显着影响啮齿动物中 GSK690693 诱导的高血糖症。然而，在小鼠中施用 GSK690693 可显着降低肝糖原（约 90%），表明 GSK690693 可抑制糖原合成和/或激活糖原分解[3]。用 Akt 抑制剂 GSK690693 中断跑步机运行的小鼠导致 PTSD 小鼠模型[5]中跑步机对海马神经发生和行为改善的影响被阻断。 AKT 抑制剂 GSK690693 可以延长果蝇的寿命，无论是从生命初期还是中年开始治疗。 GSK690693 延长寿命的作用主要与改善抗氧化性、肠道完整性和增加自噬有关，但与体力活动或抗饥饿性无关[6]。 EVI1 敲低降低了癌症干细胞样特性并改善了细胞系和皮下小鼠模型中的伊立替康反应。伊立替康和 GSK690693 联合治疗可显着降低结肠癌细胞存活率和肿瘤进展率[7]。
| Kinase experiment [1]: | |
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Preparation Method |
To more accurately measure time-dependent inhibition of Akt, activated Akt enzymes were incubated with GSK690693 at various concentrations at room temperature for 30 min before the reaction was initiated with the addition of substrate. Final reaction contains 5 to 15 nmol/L Akt1, 2, and 3 enzymes; 2 μmol/L ATP; 0.15 μCi/μL [γ 33P]ATP; 1 μmol/L Peptide; 10 mmol/L MgCl2; 25 mmol/L MOPS (pH 7.5); 1 mmol/L DTT; 1 mmol/L CHAPS; and 50 mmol/L KCl. The reactions were incubated at room temperature for 45 min, followed by termination with Leadseeker beads in PBS containing EDTA. |
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Applications |
GSK690693 is an ATP-competitive, low nanomolar inhibitor of Akt kinases with IC50 values of 2, 13, and 9 nM for Akt1, 2, and 3, respectively. The apparent Ki*s for full-length Akt1, 2, and 3 were determined as 1, 4, and 12 nM, respectively. |
| Cell experiment [2]: | |
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Cell lines |
BT474 cells |
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Preparation Method |
For Western blot analysis of various substrates of Akt phosphorylation, BT474 cells were treated with GSK690693 at concentrations ranging from 10 μmol/L to 1 nmol/L. |
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Reaction Conditions |
10 μM to 1 nM GSK690693 for 5 hours |
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Applications |
The phosphorylation of FKHR/FKHRL1, p70S6K, GSK3α/β, and PRAS40 in BT474 breast tumor cells was inhibited by GSK690693 in a dose-dependent manner. |
| Animal experiment [3]: | |
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Animal models |
8- to 12-wk-old CD1 Swiss Nude mice |
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Preparation Method |
Tumors were initiated by injection of tumor cell suspension or tumor fragments s.c. in 8- to 12-wk-old CD1 Swiss Nude mice or SCID mice. When tumors reached a volume, mice were randomized and divided into groups of 8 to 12 mice per group. GSK690693 was administered once daily at 10, 20, and 30 mg/kg by i.p. administration. |
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Dosage form |
GSK690693 was administered once daily at 10, 20, and 30 mg/kg by i.p. administration. |
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Applications |
Repeated i.p. administration (once daily for 21 days) produced significant antitumor activity in mice bearing established SKOV-3 ovarian, LNCaP prostate, and BT474 and HCC-1954 breast carcinoma xenografts. Maximal inhibition of 58% to 75% was observed at the end of dosing period with 30 mg/kg/day dose. Daily administration of GSK690693 for 21 days was well-tolerated in mice with |
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参考文献: [1]. Rhodes N, Heerding DA, et,al. Characterization of an Akt kinase inhibitor with potent pharmacodynamic and antitumor activity. Cancer Res. 2008 Apr 1;68(7):2366-74. doi: 10.1158/0008-5472.CAN-07-5783. PMID: 18381444. |
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