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C188-9 Sale

(Synonyms: TTI-101) 目录号 : GC34076

A STAT3 inhibitor

C188-9 Chemical Structure

Cas No.:432001-19-9

规格 价格 库存 购买数量
10mM (in 1mL DMSO)
¥982.00
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5mg
¥893.00
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10mg
¥1,250.00
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25mg
¥2,588.00
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50mg
¥4,106.00
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100mg
¥6,426.00
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Sample solution is provided at 25 µL, 10mM.

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实验参考方法

Cell experiment:

Cell lines are plated at 2 to 5×105 cells/mL in growth medium and treated with increasing doses of inhibitor for 24 hours. CD34+ AML cells are plated at 1 to 2×105 cells/mL in IMDM with 20% FBS and Pen/Strep, and incubated with C188-9 (0.3 to 100 μM) for 48 hours. Cells are then harvested and labeled. The fraction of spontaneous apoptosis is determined from an untreated sample and then subtracted from the drug-treated samples to yield the percentage of apoptosis attributed to drug treatment[1].

Animal experiment:

Mice[3]UM-SCC-17B cells (1.5×106) are injected into the tongues of athymic, 8-10 week old, male, nude mice. Once tumors are established, mice (20 total; 10/group) are randomized (average tumor vol ~15-20 mm3) to receive 5 times a week, intraperitoneal injections of either DMSO or C188 (50 mg/kg) or C188-9 (100 mg/kg). Tumor volumes are measured twice weekly. Average tumor volumes 6/πx (long dimension) x (short dimension)2)) are calculated and normalized to the volume at first day of treatment and plotted comparison is done by t test (* p<0.05) [3].

References:

[1]. Silva KA, et al. Inhibition of Stat3 activation suppresses caspase-3 and the ubiquitin-proteasome system, leading to preservation of muscle mass in cancer cachexia. J Biol Chem. 2015 Apr 24;290(17):11177-87.
[2]. Redell MS, et al. Stat3 signaling in acute myeloid leukemia: ligand-dependent and -independent activation and induction of apoptosis by a novel small-molecule Stat3 inhibitor. Blood. 2011 May 26;117(21):5701-9.
[3]. Bharadwaj U, et al. Small-molecule inhibition of STAT3 in radioresistant head and neck squamous cell carcinoma. Oncotarget. 2016 May 3;7(18):26307-30.

产品描述

C188-9 is a STAT3 inhibitor.1,2 It binds to the phosphotyrosyl peptide binding site in the STAT3 Src homology 2 (SH2) domain (Ki = 136 nM) and inhibits G-CSF-induced activation of STAT3 in patient-derived acute myeloid leukemia (AML) cells (IC50s = 8-18 ?M). C188-9 induces apoptosis in patient-derived AML cells (EC50s = 6-50 ?M) and reduces viability of HepG2, Huh7, and PLC/PRF/5 hepatoma cells (IC50s = 10.19, 11.27, and 11.83 ?M, respectively).2,3 In vivo, C188-9 (100 mg/kg) reduces hepatic Pten deletion-induced hepatic macro- and microsteatosis, which reduces the development of hepatocellular carcinomas in mice. C188-9 (12.5 mg/kg) increases muscle fiber size in a murine Lewis lung carcinoma model of cancer cachexia.1

1.Silva, K.A.S., Dong, J., Dong, Y., et al.Inhibition of Stat3 activation suppresses caspase-3 and the ubiquitin-proteasome system, leading to preservation of muscle mass in cancer cachexiaJ. Biol. Chem.290(17)11177-11187(2015) 2.Redell, M.S., Ruiz, M.J., Alonzo, T.A., et al.Stat3 signaling in acute myeloid leukemia: Ligand-dependent and -independent activation and induction of apoptosis by a novel small-molecule Stat3 inhibitorBlood117(21)5701-5709(2011) 3.Jung, K.H., Yoo, W., Stevenson, H.L., et al.Multifunctional effects of a small-molecule STAT3 inhibitor on NASH and hepatocellular carcinoma in miceClin. Cancer Res.23(18)5537-5546(2017)

Chemical Properties

Cas No. 432001-19-9 SDF
别名 TTI-101
Canonical SMILES O=S(C1=CC=C(OC)C=C1)(NC2=C3C=CC=CC3=C(O)C(C4=C5C=CC=CC5=CC=C4O)=C2)=O
分子式 C27H21NO5S 分子量 471.52
溶解度 DMSO : ≥ 62 mg/mL (131.49 mM) 储存条件 4°C, protect from light
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溶解性数据

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1 mg 5 mg 10 mg
1 mM 2.1208 mL 10.604 mL 21.208 mL
5 mM 0.4242 mL 2.1208 mL 4.2416 mL
10 mM 0.2121 mL 1.0604 mL 2.1208 mL
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Research Update

C188-9 reduces TGF-β1-induced fibroblast activation and alleviates ISO-induced cardiac fibrosis in mice

FEBS Open Bio 2021 Jul;11(7):2033-2040.PMID:34056872DOI:10.1002/2211-5463.13212.

Cardiac fibrosis is the final event of heart failure and is associated with almost all forms of cardiovascular disease. Cardiac fibroblasts (CFs), a major cell type in the heart, are responsible for regulating normal myocardial function and maintaining extracellular matrix homeostasis in adverse myocardial remodeling. In this study, we found that C188-9, a small-molecule inhibitor of signal transducer and activator of transcription 3 (STAT3), exhibited an antifibrotic function, both in vitro and in vivo. C188-9 decreased transforming growth factor-β1-induced CF activation and fibrotic gene expression. Moreover, C188-9 treatment alleviated heart injury and cardiac fibrosis in an isoproterenol-induced mouse model by suppressing STAT3 phosphorylation and activation. These findings may help us better understand the role of C188-9 in cardiac fibrosis and facilitate the development of new treatments for cardiac fibrosis and other cardiovascular diseases.

C188-9, a specific inhibitor of STAT3 signaling, prevents thermal burn-induced skeletal muscle wasting in mice

Front Pharmacol 2022 Dec 16;13:1031906.PMID:36588738DOI:10.3389/fphar.2022.1031906.

Burn injury is the leading cause of death and disability worldwide and places a tremendous economic burden on society. Systemic inflammatory responses induced by thermal burn injury can cause muscle wasting, a severe involuntary loss of skeletal muscle that adversely affects the survival and functional outcomes of these patients. Currently, no pharmacological interventions are available for the treatment of thermal burn-induced skeletal muscle wasting. Elevated levels of inflammatory cytokines, such as interleukin-6 (IL-6), are important hallmarks of severe burn injury. The levels of signal transducer and activator of transcription 3 (STAT3)-a downstream component of IL-6 inflammatory signaling-are elevated with muscle wasting in various pro-catabolic conditions, and STAT3 has been implicated in the regulation of skeletal muscle atrophy. Here, we tested the effects of the STAT3-specific signaling inhibitor C188-9 on thermal burn injury-induced skeletal muscle wasting in vivo and on C2C12 myotube atrophy in vitro after the administration of plasma from burn model mice. In mice, thermal burn injury severity dependently increased IL-6 in the plasma and tibialis anterior muscles and activated the STAT3 (increased ratio of phospho-STAT3/STAT3) and ubiquitin-proteasome proteolytic pathways (increased Atrogin-1/MAFbx and MuRF1). These effects resulted in skeletal muscle atrophy and reduced grip strength. In murine C2C12 myotubes, plasma from burn mice activated the same inflammatory and proteolytic pathways, leading to myotube atrophy. In mice with burn injury, the intraperitoneal injection of C188-9 (50 mg/kg) reduced activation of the STAT3 and ubiquitin-proteasome proteolytic pathways, reversed skeletal muscle atrophy, and increased grip strength. Similarly, pretreatment of murine C2C12 myotubes with C188-9 (10 µM) reduced activation of the same inflammatory and proteolytic pathways, and ameliorated myotube atrophy induced by plasma taken from burn model mice. Collectively, these results indicate that pharmacological inhibition of STAT3 signaling may be a novel therapeutic strategy for thermal burn-induced skeletal muscle wasting.

C188-9, a small-molecule STAT3 inhibitor, exerts an antitumor effect on head and neck squamous cell carcinoma

Anticancer Drugs 2019 Sep;30(8):846-853.PMID:30870229DOI:10.1097/CAD.0000000000000783.

Abnormal activation of signal transducer and activator of transcription 3 (STAT3) is complicated in the tumor progression of multiple cancers including human head and neck squamous cell carcinoma (HNSCC) and, therefore, serves as a potent therapeutic target. In this study, we identify that C188-9, a small-molecule STAT3 inhibitor, exhibits an antitumor effect on HNSCC in vitro. C188-9 significantly inhibits cell growth, arrests cell cycle at G0/G1 phase, and induces apoptosis in HNSCC. Besides, the capacities of migration and invasion of HNSCC cells are impaired with the exposure to C188-9. In addition, C188-9 treatment enhanced the chemosensitivity of HNSCC cellsin vitro. Moreover, C188-9 inactivates STAT3 by reducing its phosphorylation at Tyr705. Taken together, these results indicate that C188-9 could be a promising therapeutic strategy for patients suffered from HNSCC by suppressing the STAT3 pathway.

IL-6/STAT3 Is a Promising Therapeutic Target for Hepatocellular Carcinoma

Front Oncol 2021 Dec 15;11:760971.PMID:34976809DOI:10.3389/fonc.2021.760971.

Hepatocellular carcinoma (HCC) is a common malignant tumor of which the occurrence and development, the tumorigenicity of HCC is involving in multistep and multifactor interactions. Interleukin-6 (IL-6), a multifunctional inflammatory cytokine, has increased expression in HCC patients and is closely related to the occurrence of HCC and prognosis. IL-6 plays a role by binding to the IL-6 receptor (IL-6R) and then triggering the Janus kinase (JAK) associated with the receptor, stimulating phosphorylation and activating signal transducer and activator of transcription 3 (STAT3) to initiate downstream signals, participating in the processes of anti-apoptosis, angiogenesis, proliferation, invasion, metastasis, and drug resistance of cancer cells. IL-6/STAT3 signal axes elicit an immunosuppressive in tumor microenvironment, it is important to therapy HCC by blocking the IL-6/STAT3 signaling pathway. Recent, some inhibitors of IL-6/STAT3 have been development, such as S31-201 or IL-6 neutralizing monoclonal antibody (IL-6 mAb), Madindoline A (Inhibits the dimerization of IL-6/IL-6R/gpl30 trimeric complexes), C188-9 and Curcumin (Inhibits STAT3 phosphorylation), etc. for treatment of cancers. Overall, consideration of the IL-6/STAT3 signaling pathway, and its role in the carcinogenesis and progression of HCC will contribute to the development of potential drugs for targeting treatment of liver cancer.

Small Molecule Inhibitor C188-9 Synergistically Enhances the Demethylated Activity of Low-Dose 5-Aza-2'-Deoxycytidine Against Pancreatic Cancer

Front Oncol 2020 May 8;10:612.PMID:32457835DOI:10.3389/fonc.2020.00612.

Aberrant DNA methylation, especially hypermethylation of tumor suppressor genes, has been associated with many cancers' progression. 5-Aza-2'-deoxycytidine (DAC) can reverse hypermethylation-induced gene silencing via regulating DNA methyltransferases (DNMTs) activity, In addition, low-dose of DAC was proved to exert durable antitumor effects against solid tumor cells. Nevertheless, no clinical effect of DAC has been made when fighting against pancreatic cancer. Hence, it is necessary to raise a novel therapeutic strategy that further enhance the efficacy of DAC but not increase side effect, which impede the utilization of DAC. In the present study, we have discovered that C188-9, a novel signal transduction activator of transcription (STAT) inhibitor, could improve the antitumor effects of low-dose DAC in vivo and in vitro. Further study demonstrated that such improvement was attributed to re-expression of Ras association domain family member 1A (RASSF1A), a well-known tumor suppressor gene. Bisulfite sequencing PCR (BSP) assay showed that C188-9 combined with DAC treatment could significantly reverse the hypermethylation status of RASSF1A promoter, which indicated that C188-9 could enhance the demethylation efficacy of DAC. Our data demonstrated that DNA methyltransferase 1 (DNMT1) was the underlying mechanism that C188-9 regulates the demethylation efficacy of DAC. Overall, these findings provide a novel therapeutic strategy combining low-dose DAC and C188-9 to improve therapeutic efficacy by inhibiting DNMT1-inducing promoter methylation.