GSK8612
目录号 : GC65013
A TBK1 inhibitor
Cas No.:2361659-62-1
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
TBK1 6.8(pIC50) |
GSK8612 is an inhibitor of TANK-binding kinase 1 (TBK1; IC50 = 158 nM).1 It is selective for TBK1 over a panel of 285 kinases. GSK8612 inhibits IFN-α release in isolated human peripheral blood mononuclear cells (PBMCs) stimulated with polyinosinic-polycytidylic acid (poly(I:C); IC50 = 794 nM). It also inhibits IFN-β secretion in THP-1 cells stimulated with dsDNA-containing baculovirus or cGAMP (IC50s = 1,258 and 501 nM, respectively). GSK8612 (5 mg/kg) reduces tumor volume and increases the number of tumor-infiltrating CD8+ T cells in immunocompetent, but not immunodeficient, mice in a model of carbon tetrachloride-induced hepatocellular carcinoma (HCC).2
1.Thomson, D.W., Poeckel, D., Zinn, N., et al.Discovery of GSK8612, a highly selective and potent TBK1 inhibitorMed. Chem. Lett.10(5)780-785(2019) 2.Jiang, Y., Chen, S., Li, Q., et al.TANK-binding kinase 1 (TBK1) serves as a potential target for hepatocellular carcinoma by enhancing tumor immune infiltrationFront. Immunol.12612139(2021)
| Cas No. | 2361659-62-1 | SDF | Download SDF |
| 分子式 | C17H17BrF3N7O2S | 分子量 | 520.33 |
| 溶解度 | DMSO : ≥ 125 mg/mL (240.23 mM) | 储存条件 | -20°C, protect from light |
| 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 | 1.9219 mL | 9.6093 mL | 19.2186 mL |
| 5 mM | 0.3844 mL | 1.9219 mL | 3.8437 mL |
| 10 mM | 0.1922 mL | 0.9609 mL | 1.9219 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。
Discovery of GSK8612, a Highly Selective and Potent TBK1 Inhibitor
ACS Med Chem Lett 2019 Mar 11;10(5):780-785.PMID:31097999DOI:10.1021/acsmedchemlett.9b00027.
The serine/threonine protein kinase TBK1 (Tank-binding Kinase-1) is a noncanonical member of the IkB kinase (IKK) family. This kinase regulates signaling pathways in innate immunity, oncogenesis, energy homeostasis, autophagy, and neuroinflammation. Herein, we report the discovery and characterization of a novel potent and highly selective TBK1 inhibitor, GSK8612. In cellular assays, this small molecule inhibited toll-like receptor (TLR)3-induced interferon regulatory factor (IRF)3 phosphorylation in Ramos cells and type I interferon (IFN) secretion in primary human mononuclear cells. In THP1 cells, GSK8612 was able to inhibit secretion of interferon beta (IFNβ) in response to dsDNA and cGAMP, the natural ligand for STING. GSK8612 is a TBK1 small molecule inhibitor displaying an excellent selectivity profile and therefore represents an ideal probe to further dissect the biology of TBK1 in models of immunity, neuroinflammation, obesity, or cancer.
Pharmacological Inhibition of STING/TBK1 Signaling Attenuates Myeloid Fibroblast Activation and Macrophage to Myofibroblast Transition in Renal Fibrosis
Front Pharmacol 2022 Jul 18;13:940716.PMID:35924048DOI:10.3389/fphar.2022.940716.
Renal fibrosis is an important pathological biomarker of chronic kidney disease (CKD). Stimulator of interferon genes/TANK binding kinase 1 (STING/TBK1) axis has been identified as the main regulator of innate immune response and closely related to fibrotic disorder. However, the role of STING/TBK1 signaling pathway in kidney fibrosis is still unknown. In this study, we investigated the effect of pharmacological inhibition of STING/TBK1 signaling on renal fibrosis induced by folic acid (FA). In mice, TBK1 was significantly activated in interstitial cells of FA-injured kidneys, which was markedly inhibited by H-151 (a STING inhibitor) treatment. Specifically, pharmacological inhibition of STING impaired bone marrow-derived fibroblasts activation and macrophage to myofibroblast transition in folic acid nephropathy, leading to reduction of extracellular matrix proteins expression, myofibroblasts formation and development of renal fibrosis. Furthermore, pharmacological inhibition of TBK1 by GSK8612 reduced myeloid myofibroblasts accumulation and impeded macrophage to myofibroblast differentiation, resulting in less deposition of extracellular matrix protein and less severe fibrotic lesion in FA-injured kidneys. In cultured mouse bone marrow-derived monocytes, TGF-β1 activated STING/TBK1 signaling. This was abolished by STING or TBK1 inhibitor administration. In addition, GSK8612 treatment decreased levels of α-smooth muscle actin and extracellular matrix proteins and prevents bone marrow-derived macrophages to myofibroblasts transition in vitro. Collectively, our results revealed that STING/TBK1 signaling has a critical role in bone marrow-derived fibroblast activation, macrophages to myofibroblasts transition, and kidney fibrosis progression.
TANK-binding kinase 1 inhibitor GSK8612 enhances daunorubicin sensitivity in acute myeloid leukemia cells via the AKT-CDK2 pathway
Am J Transl Res 2021 Dec 15;13(12):13640-13653.PMID:35035703doi
Purpose: It has been established in previous studies that TANK-binding kinase 1 (TBK1) is upregulated in malignant tumors and is therefore associated with poor prognosis. However, the role of TBK1 in acute myeloid leukemia (AML) remains unclear. In this study, we investigated the expression levels and the function of TBK1 in AML. Methods: First, TBK1 expression was detected and analyzed using Western blot and qRT-PCR. Then, GSK8612, a novel TBK1 inhibitor, and TBK1-specific siRNA (si-TBK1) were used to inhibit TBK1 function and expression. The effects of TBK1 inhibition on AML were investigated first through a cell counting kit (CCK-8) assay, followed by trypan blue staining to assess cell apoptosis and cell cycle progression in vitro. Finally, the signaling pathway activities in HL-60 and Kasumi-1 cells and patients' mononuclear cells (MNCs) were explored using western blot. Results: We found a significantly higher TBK1 expression in AML patients with poor prognoses. GSK8612 successfully inhibited TBK1 expression, resulting in the increased sensitivity of AML cells to daunorubicin. Mechanistically, TBK1 inhibition (by GSK8612 and si-TBK1) regulated cyclin-dependent kinase 2 (CDK2) levels in AML cells via the AKT pathway. Moreover, it was observed that the inhibition of protein kinase B (AKT) activity also resulted in the increased sensitivity of AML cell lines to daunorubicin, validating the relationship between TBK1 and the AKT-CDK2 pathway. Similar results were obtained in MNCs from patients with AML. Conclusion: TBK1 is a potential prognostic factor for AML, and its inhibition may improve the sensitivity of AML cells to daunorubicin. This regulatory effect is predicted to involve the TBK1-AKT-CDK2 pathway.
Therapeutic targeting of TANK-binding kinase signaling towards anticancer drug development: Challenges and opportunities
Int J Biol Macromol 2022 May 15;207:1022-1037.PMID:35358582DOI:10.1016/j.ijbiomac.2022.03.157.
TANK-binding kinase 1 (TBK1) plays a fundamental role in regulating the cellular responses and controlling several signaling cascades. It regulates inflammatory, interferon, NF-κB, autophagy, and Akt pathways. Post-translational modifications (PTM) of TBK1 control its action and subsequent cellular signaling. The dysregulation of the TBK1 pathway is correlated to many pathophysiological conditions, including cancer, that implicates the promising therapeutic advantage for targeting TBK1. The present study summarizes current updates on the molecular mechanisms and cancer-inducing roles of TBK1. Designed inhibitors of TBK1 are considered a potential therapeutic agent for several diseases, including cancer. Data from pre-clinical tumor models recommend that the targeting of TBK1 could be an attractive strategy for anti-tumor therapy. This review further highlighted the therapeutic potential of potent and selective TBK1 inhibitors, including Amlexanox, Compound II, BX795, MRT67307, SR8185 AZ13102909, CYT387, GSK8612, BAY985, and Domainex. These inhibitors may be implicated to facilitate therapeutic management of cancer and TBK1-associated diseases in the future.