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9-ING-41 Sale

(Synonyms: Elraglusib) 目录号 : GC39152

A GSK3β inhibitor

9-ING-41 Chemical Structure

Cas No.:1034895-42-5

规格 价格 库存 购买数量
10mM (in 1mL DMSO)
¥924.00
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5mg
¥840.00
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10mg
¥1,400.00
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25mg
¥2,940.00
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50mg
¥5,250.00
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100mg
¥9,100.00
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产品描述

9-ING-41 is an inhibitor of glycogen synthase kinase 3β (GSK3β; IC50 = 0.71 ?M).1 It inhibits the growth of MiaPaCa-2, BxPC-3, and HuP-T3 pancreatic cancer cells (IC50s = 5, 1, and 0.6 ?M, respectively). 9-ING-41 (5 ?M) inhibits GSK3β phosphorylation and induces apoptosis in BxPC-3 and HuP-T3 cells. In vivo, 9-ING-41 (40 mg/kg) reduces tumor growth in an SKOV3 mouse xenograft model.2 It also reduces pleural thickening and improves lung function in a mouse model of S. pneumoniae-induced empyema.3

1.Gaisina, I.N., Gallier, F., Ougolkov, A.V., et al.From a natural product lead to the identification of potent and selective benzofuran-3-yl-(indol-3-yl)maleimides as glycogen synthase kinase 3β inhibitors that suppress proliferation and survival of pancreatic cancer cellsJ. Med. Chem.52(7)1853-1863(2009) 2.Hilliard, T.S., Gaisina, I.N., Muehlbauer, A.G., et al.Glycogen synthase kinase 3 beta inhibitors induce apoptosis in ovarian cancer cells and inhibit in vivo tumor growthAnticancer Drugs22(10)978-985(2011) 3.Boren, J., Shryock, G., Fergis, A., et al.Inhibition of glycogen synthase kinase 3β blocks mesomesenchymal transition and attenuates Streptococcus pneumonia-mediated pleural injury in miceAm. J. Pathol.187(11)2461-2472(2017)

Chemical Properties

Cas No. 1034895-42-5 SDF
别名 Elraglusib
Canonical SMILES O=C(C(C1=COC2=CC=C(F)C=C12)=C3C4=CN(C)C5=C4C=C6C(OCO6)=C5)NC3=O
分子式 C22H13FN2O5 分子量 404.35
溶解度 DMSO: 250 mg/mL (618.28 mM) 储存条件 Store at -20°C
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1 mM 2.4731 mL 12.3655 mL 24.731 mL
5 mM 0.4946 mL 2.4731 mL 4.9462 mL
10 mM 0.2473 mL 1.2366 mL 2.4731 mL
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Research Update

9-ING-41, a Small Molecule Inhibitor of GSK-3β, Potentiates the Effects of Chemotherapy on Colorectal Cancer Cells

Front Pharmacol 2021 Dec 9;12:777114.PMID:34955846DOI:10.3389/fphar.2021.777114.

Colorectal cancer (CRC) is one of the most common and lethal types of cancer. Although researchers have made significant efforts to study the mechanisms underlying CRC drug resistance, our knowledge of this disease is still limited, and novel therapies are in high demand. It is urgent to find new targeted therapy considering limited chemotherapy options. KRAS mutations are the most frequent molecular alterations in CRC. However, there are no approved K-Ras targeted therapies for these tumors yet. GSK-3β is demonstrated to be a critically important kinase for the survival and proliferation of K-Ras-dependent pancreatic cancer cells. In this study, we tested combinations of standard-of-care therapy and 9-ING-41, a small molecule inhibitor of GSK-3β, in CRC cell lines and patient-derived tumor organoid models of CRC. We demonstrate that 9-ING-41 inhibits the growth of CRC cells via a distinct from chemotherapy mechanism of action. Although molecular biomarkers of 9-ING-41 efficacy are yet to be identified, the addition of 9-ING-41 to the standard-of-care drugs 5-FU and oxaliplatin could significantly enhance growth inhibition in certain CRC cells. The results of the transcriptomic analysis support our findings of cell cycle arrest and DNA repair deficiency in 9-ING-41-treated CRC cells. Notably, we find substantial similarity in the changes of the transcriptomic profile after inhibition of GSK-3β and suppression of STK33, another critically important kinase for K-Ras-dependent cells, which could be an interesting point for future research. Overall, the results of this study provide a rationale for the further investigation of GSK-3 inhibitors in combination with standard-of-care treatment of CRC.

GSK-3β in Pancreatic Cancer: Spotlight on 9-ING-41, Its Therapeutic Potential and Immune Modulatory Properties

Biology (Basel) 2021 Jul 1;10(7):610.PMID:34356465DOI:10.3390/biology10070610.

Glycogen synthase kinase-3 beta is a ubiquitously and constitutively expressed molecule with pleiotropic function. It acts as a protooncogene in the development of several solid tumors including pancreatic cancer through its involvement in various cellular processes including cell proliferation, survival, invasion and metastasis, as well as autophagy. Furthermore, the level of aberrant glycogen synthase kinase-3 beta expression in the nucleus is inversely correlated with tumor differentiation and survival in both in vitro and in vivo models of pancreatic cancer. Small molecule inhibitors of glycogen synthase kinase-3 beta have demonstrated therapeutic potential in pre-clinical models and are currently being evaluated in early phase clinical trials involving pancreatic cancer patients with interim results showing favorable results. Moreover, recent studies support a rationale for the combination of glycogen synthase kinase-3 beta inhibitors with chemotherapy and immunotherapy, warranting the evaluation of novel combination regimens in the future.

9-ING-41, a small-molecule glycogen synthase kinase-3 inhibitor, is active in neuroblastoma

Anticancer Drugs 2018 Sep;29(8):717-724.PMID:29846250DOI:10.1097/CAD.0000000000000652.

Advanced stage neuroblastoma is a very aggressive pediatric cancer with limited treatment options and a high mortality rate. Glycogen synthase kinase-3β (GSK-3β) is a potential therapeutic target in neuroblastoma. Using immunohistochemical staining, we observed positive GSK-3β expression in 67% of human neuroblastomas (34 of 51 cases). Chemically distinct GSK-3 inhibitors (AR-A014418, TDZD-8, and 9-ING-41) suppressed the growth of neuroblastoma cells, whereas 9-ING-41, a clinically relevant small-molecule GSK-3β inhibitor with broad-spectrum preclinical antitumor activity, being the most potent. Inhibition of GSK-3 resulted in a decreased expression of the antiapoptotic molecule XIAP and an increase in neuroblastoma cell apoptosis. Mouse xenograft studies showed that the combination of clinically relevant doses of CPT-11 and 9-ING-41 led to greater antitumor effect than was observed with either agent alone. These data support the inclusion of patients with advanced neuroblastoma in clinical studies of 9-ING-41, especially in combination with CPT-11.

9-ING-41, a small molecule inhibitor of GSK-3beta, potentiates the effects of anticancer therapeutics in bladder cancer

Sci Rep 2019 Dec 27;9(1):19977.PMID:31882719DOI:10.1038/s41598-019-56461-4.

Glycogen synthase kinase-3 beta (GSK-3β), a serine/threonine kinase, has been identified as a potential therapeutic target in human bladder cancer. In the present study, we investigated the antitumor effect of a small molecule GSK-3β inhibitor, 9-ING-41, currently in clinical studies in patients with advanced cancer, in bladder cancer cell lines. We found that treatment with 9-ING-41 leads to cell cycle arrest, autophagy and apoptosis in bladder cancer cells. The autophagy inhibitor chloroquine potentiated the antitumor effects of 9-ING-41 when tested in combination studies. Our findings also demonstrate that 9-ING-41 enhanced the growth inhibitory effects of gemcitabine or cisplatin when used in combination in bladder cancer cells. Finally, we found that 9-ING-41 sensitized bladder cancer cells to the cytotoxic effects of human immune effector cells. Our results provide a rationale for the inclusion of patients with advanced bladder cancer in clinical studies of 9-ING-41.

Malignant glioma subset from actuate 1801: Phase I/II study of 9-ING-41, GSK-3β inhibitor, monotherapy or combined with chemotherapy for refractory malignancies

Neurooncol Adv 2022 Feb 7;4(1):vdac012.PMID:35402914DOI:10.1093/noajnl/vdac012.

Background: GSK3β serine/threonine kinase regulates metabolism and glycogen biosynthesis. GSK3β overexpression promotes progression and resistance through NF-κB and p53 apoptotic pathways. GSK3β inhibits immunomodulation by downregulating PD-L1 and LAG-3 checkpoints and increasing NK and T-cell tumor killing. 9-ING-41, a small-molecule, selective GSK3β inhibitor, showed preclinical activity in chemo-resistant PDX glioblastoma models, including enhanced lomustine antitumor effect. Methods: Refractory malignancies (n = 162) were treated with 9-ING-41 monotherapy (n = 65) or combined with 8 cytotoxic regimens after prior exposure (NCT03678883). Recurrent gliomas (n = 18) were treated with 9-ING-41 IV TIW q21day cycles at 3.3, 5, 9.3, 15 mg/kg, as monotherapy or combined with lomustine 30 mg/m² PO weekly q84day cycles. Primary objective was safety. Results: RP2D of 15 mg/kg IV TIW was confirmed across all 9 regimens, no accentuated chemotherapy toxicity noted. Glioma subtypes included: 13 glioblastoma, 2 anaplastic astrocytomas, 1 anaplastic oligodendroglioma, 1 astrocytoma. Median age 52 (30-69) years; 6 female, 12 male; median ECOG 1 (0-2); median recurrences 3 (1-6). All received upfront radiation/temozolomide (18/18), plus salvage nitrosoureas (15/18), bevacizumab (8/18), TTFields (6/18), or immunotherapy (4/18). IDH/mutation(3/18); 1p19q/codeletion(1/18); MGMT/methylated(1/18). Four received 9-ING-41 monotherapy, 14 concurrent with lomustine. No severe toxicities were attributed to 9-ING-41, only mild vision changes (9/18, 50%), or infusion reactions (4/18, 22%). Lomustine-related toxicities: G3/4 thrombocytopenia (3/14, 21%), G1/2 fatigue (4/14, 28%). Median days on therapy was 55 (4-305); 1 partial response (>50%) was noted. Median OS was 5.5 (95% CI: 2.8-11.4) months and PFS-6 was 16.7%. Conclusion: 9-ING-41 plus/minus lomustine is safe and warrants further study in glioma patients.