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Purity: ≥98%
C188-9 is a novel, potent and orally bioavailable STAT3 inhibitor that binds to STAT3 with high affinity (KD=4.7±0.4 nM). It is a small-molecule inhibitor that targets the phosphotyrosyl peptide binding site within the Stat3 Src homology 2 (SH2) domain with Ki 136 nM. It does not inhibit upstream Jak or Src kinase. C188-9 is well tolerated in mice, has good oral bioavailability, and is concentrated in tumors. STAT3 inhibition by C188-9 resulted in attenuated skin fibrosis, myofibroblast accumulation, pro-fibrotic gene expression and collagen deposition in both mouse models of skin fibrosis. C188-9 decreased in vitro dermal fibroblast production of fibrotic genes induced by IL-6 trans-signalling and TGF-β. Finally, TGF-β induced phosphotyrosylation of STAT3 in a SMAD3-dependent manner.
| ln Vitro |
C188-9 (Kd = 4.7 nM) is a Stat3 inhibitor [1]. The range of 4-7 μM and 8-18 μM is where C188-9's IC50s for inhibiting Stat3 activation in AML cell lines and primary AML samples are found. In order to measure apoptotic cells for annexin V-labeled cells in apoptosis investigations, C188-9 is applied to AML cell lines and primary samples for a duration of 24 hours. From 6 μM to over 50 μM, the EC50s for inducing apoptosis exhibit significant variability [2].
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| ln Vivo |
Out of the roughly 13,528 distinguishable genes, C188 modifies the levels of 37 gene transcripts (17 down-regulated and 20 up-regulated, fdr <0.01, fold change≥1.5), 7 of which are identified as STAT3 gene targets. 76 genes that were previously identified as being regulated by STAT3 (38 down-regulated and 38 up-regulated) are among the much larger number of oncogenesis-related genes that C188-9 affects (384 total, 95 down- and 289 up-regulated). Naturally, C188-9 treatment results in the downregulation of 24 (63%) of the 38 genes that have been previously reported to be upregulated by STAT3. Furthermore, C188-9 downregulated 10 additional genes (fdr <0.01, fold change ≥1.5) that had previously been demonstrated to be upregulated by STAT1. Thus, STAT1 has been shown to positively regulate 40 of 48 (83.3%) genes that were previously downregulated by C188-9, including sixteen genes that have been demonstrated to be co-regulated by STAT3 and STAT1. This analysis suggests that C188-9 may affect both STAT3 and STAT1 in order to mediate its effect on gene transcript levels in HNSCC tumors[3].
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| 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. [4]. 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;117(21):5701-5709 |
| Molecular Formula |
C27H21NO5S
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| Molecular Weight |
471.52
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| CAS # |
432001-19-9
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| SMILES |
O=S(C1=CC=C(OC)C=C1)(NC2=C3C=CC=CC3=C(O)C(C4=C5C=CC=CC5=CC=C4O)=C2)=O
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| Synonyms |
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.41 mM) (saturation unknown) in 10% DMSO + 40% PEG300 +5% Tween-80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 + to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1208 mL | 10.6040 mL | 21.2080 mL | |
| 5 mM | 0.4242 mL | 2.1208 mL | 4.2416 mL | |
| 10 mM | 0.2121 mL | 1.0604 mL | 2.1208 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
Structure Activity Relationship (SAR) of C188 and similar compounds.Oncotarget.2016 May 3;7(18):26307-30. |
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Inhibition of STAT3 activities by C188 and C188-9.Oncotarget.2016 May 3;7(18):26307-30. |
C188-9 binds to STAT3 with high affinity.Oncotarget.2016 May 3;7(18):26307-30. |
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