GSK690693
(Synonyms: 4-[2-(4-氨基-1,2,5-恶二唑-3-基)-1-乙基-7-[(3S)-3-哌啶基甲氧基]-1H-咪唑并[4,5-C]吡啶-4-基]-2-甲基-3-丁炔-2-醇) 目录号 : GC13696
An Akt inhibitor
Cas No.:937174-76-0
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| 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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References: [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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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].
References:
[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]。
| Cas No. | 937174-76-0 | SDF | |
| 别名 | 4-[2-(4-氨基-1,2,5-恶二唑-3-基)-1-乙基-7-[(3S)-3-哌啶基甲氧基]-1H-咪唑并[4,5-C]吡啶-4-基]-2-甲基-3-丁炔-2-醇 | ||
| 化学名 | 4-[2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-[[(3S)-piperidin-3-yl]methoxy]imidazo[4,5-c]pyridin-4-yl]-2-methylbut-3-yn-2-ol | ||
| Canonical SMILES | CCN1C2=C(C(=NC=C2OCC3CCCNC3)C#CC(C)(C)O)N=C1C4=NON=C4N | ||
| 分子式 | C21H27N7O3 | 分子量 | 425.48 |
| 溶解度 | ≥ 21.25mg/mL in DMSO | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.3503 mL | 11.7514 mL | 23.5029 mL |
| 5 mM | 0.4701 mL | 2.3503 mL | 4.7006 mL |
| 10 mM | 0.235 mL | 1.1751 mL | 2.3503 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Inhibitor GSK690693 extends Drosophila lifespan via reduce AKT signaling pathway
Aging is a process involving physiological changes that lead to the decline of biological functions of various tissues and organs of the body. Therefore, it is crucial to find anti-aging drugs that can intervene with the changes induced because of aging and slow down the degeneration of the biological functions. Among many signaling pathways linked with aging and aging-related diseases, PI3K-AKT signaling pathway has attracted major attention in aging biology. In this research paper, we have demonstrated that 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. Furthermore, GSK690693 treatment reduced the activation of AKT and ERK, consequently activating FOXO, GSK-3β and apoptosis to modulate longevity of flies. Remarkably, GSK690693 did not induce hyperglycemia after treatment. The results indicate that GSK690693 may become an effective compound for anti-aging intervention.
Akt signalling in health and disease
Akt (also known as protein kinase B or PKB) comprises three closely related isoforms Akt1, Akt2 and Akt3 (or PKBα/β/γ respectively). We have a very good understanding of the mechanisms by which Akt isoforms are activated by growth factors and other extracellular stimuli as well as by oncogenic mutations in key upstream regulatory proteins including Ras, PI3-kinase subunits and PTEN. There are also an ever increasing number of Akt substrates being identified that play a role in the regulation of the diverse array of biological effects of activated Akt; this includes the regulation of cell proliferation, survival and metabolism. Dysregulation of Akt leads to diseases of major unmet medical need such as cancer, diabetes, cardiovascular and neurological diseases. As a result there has been substantial investment in the development of small molecular Akt inhibitors that act competitively with ATP or phospholipid binding, or allosterically. In this review we will briefly discuss our current understanding of how Akt isoforms are regulated, the substrate proteins they phosphorylate and how this integrates with the role of Akt in disease. We will furthermore discuss the types of Akt inhibitors that have been developed and are in clinical trials for human cancer, as well as speculate on potential on-target toxicities, such as disturbances of heart and vascular function, metabolism, memory and mood, which should be monitored very carefully during clinical trial.
GSK690693 delays tumor onset and progression in genetically defined mouse models expressing activated Akt
Purpose: Akt plays a central role in regulating tumor cell survival and cell cycle progression and is regarded as a promising therapeutic target. We used genetically defined mouse models that develop spontaneous tumors exhibiting activated Akt to determine if Akt inhibition by GSK690693 is effective in the treatment of cancer. The broad long-term objective of this project was to use preclinical cancer models with precisely defined genetic lesions to elucidate the efficacy of targeting Akt with GSK690693.
Experimental design: We tested the in vivo effects of GSK690693 in Lck-MyrAkt2 transgenic mice that develop lymphomas, heterozygous Pten(+/-) knockout mice that exhibit endometrial tumors, and TgMISIIR-TAg-DR26 mice that develop ovarian carcinomas, all of which exhibit hyperactivation of Akt. In addition to standard disease onset and histology, tumors arising in treated animals were examined by immunohistochemistry to verify downregulated Akt signaling relative to placebo-treated mice. When possible, drug response was evaluated in tumor cell cultures by standard proliferation and apoptosis assays and by immunoblotting with various phosphospecific antibodies.
Results: GSK690693 exhibited efficacy irrespective of the mechanism of Akt activation involved. Interestingly, 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.
Conclusion: These results suggest that GSK690693 or other Akt inhibitors might have therapeutic efficacy in human cancers with hyperactivated Akt and/or a dependence on Akt signaling for tumor progression.
ZIP10 drives osteosarcoma proliferation and chemoresistance through ITGA10-mediated activation of the PI3K/AKT pathway
Background: The zinc transporters Zrt- and Irt-related protein (ZIP/SLC39) are overexpressed in human tumors and correlate with poor prognosis; however, their contributions to carcinogenesis and chemoresistance in osteosarcoma (OS) remain unclear.
Methods: We collected 64 OS patient tissues with (n = 12) or without (n = 52) chemotherapy. The expression levels of ZIP10 were measured by immunohistochemistry and applied to prognostic analysis. ZIP10 was knocked down or overexpressed in OS cell lines to explore its effect on proliferation and chemoresistance. RNA sequencing, quantitative real-time PCR, and western blotting analysis were performed to explore ZIP10-regulated downstream target genes. A xenograft mouse model was established to evaluate the mechanisms by which ZIP10 modulates chemoresistance in OS cells.
Results: The expression of ZIP10 was significantly induced by chemotherapy and highly associated with the clinical outcomes of OS. Knockdown of ZIP10 suppressed OS cell proliferation and chemoresistance. In addition, ZIP10 promoted Zn content-induced cAMP-response element binding protein (CREB) phosphorylation and activation, which are required for integrin α10 (ITGA10) transcription and ITGA10-mediated PI3K/AKT pathway activation. Importantly, ITGA10 stimulated PI3K/AKT signaling but not the classical FAK or SRC pathway. Moreover, overexpression of ZIP10 promoted ITGA10 expression and conferred chemoresistance. Treatment with the CREB inhibitor 666-15 or the PI3K/AKT inhibitor GSK690693 impaired tumor chemoresistance in ZIP10-overexpressing cells. Finally, a xenograft mouse model established by subcutaneous injection of 143B cells confirmed that ZIP10 mediates chemotherapy resistance in OS cells via the ZIP10-ITGA10-PI3K/AKT axis.
Conclusions: We demonstrate that ZIP10 drives OS proliferation and chemoresistance through ITGA10-mediated activation of the PI3K/AKT pathway, which might serve as a target for OS treatment.
Targeting the BRD4/FOXO3a/CDK6 axis sensitizes AKT inhibition in luminal breast cancer
BRD4 assembles transcriptional machinery at gene super-enhancer regions and governs the expression of genes that are critical for cancer progression. However, it remains unclear whether BRD4-mediated gene transcription is required for tumor cells to develop drug resistance. Our data show that prolonged treatment of luminal breast cancer cells with AKT inhibitors induces FOXO3a dephosphorylation, nuclear translocation, and disrupts its association with SirT6, eventually leading to FOXO3a acetylation as well as BRD4 recognition. Acetylated FOXO3a recognizes the BD2 domain of BRD4, recruits the BRD4/RNAPII complex to the CDK6 gene promoter, and induces its transcription. Pharmacological inhibition of either BRD4/FOXO3a association or CDK6 significantly overcomes the resistance of luminal breast cancer cells to AKT inhibitors in vitro and in vivo. Our study reports the involvement of BRD4/FOXO3a/CDK6 axis in AKTi resistance and provides potential therapeutic strategies for treating resistant breast cancer.