WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 540229
Description: C188-9 is a STAT3 inhibitor. HDM-induced airway inflammation, remodeling, and Th2/Th17-type cell accumulation involve STAT3 activation that can be prevented by C188-9 treatment. STAT3 inhibition with 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.
MedKoo Cat#: 540229
Chemical Formula: C27H21NO5S
Exact Mass: 471.114
Molecular Weight: 471.52
Elemental Analysis: C, 68.78; H, 4.49; N, 2.97; O, 16.97; S, 6.80
Synonym: C188-9; C 188-9; C-188-9; C-1889; C1889; C 1889; C-1889; F0808-0084;
IUPAC/Chemical Name: N-(1',2-dihydroxy-[1,2'-binaphthalen]-4'-yl)-4-methoxybenzenesulfonamide
InChi Key: QDCJDYWGYVPBDO-UHFFFAOYSA-N
InChi Code: InChI=1S/C27H21NO5S/c1-33-18-11-13-19(14-12-18)34(31,32)28-24-16-23(27(30)22-9-5-4-8-21(22)24)26-20-7-3-2-6-17(20)10-15-25(26)29/h2-16,28-30H,1H3
SMILES Code: O=S(C1=CC=C(OC)C=C1)(NC2=C3C=CC=CC3=C(O)C(C4=C5C=CC=CC5=CC=C4O)=C2)=O
Appearance: Pinky beige solid powder
Purity: >98% (or refer to the Certificate of Analysis)
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility: Soluble in DMSO
Shelf Life: >2 years if stored properly
Drug Formulation: This drug may be formulated in DMSO
Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code: 2934.99.9001
|Biological target:||C188-9 is a STAT3 inhibitor, with a Kd of 4.7 nM. C188-9 inhibits G-CSF-induced STAT3 activation and STAT3-dependent gene expression.|
|In vitro activity:||To evaluate the effect of C188-9 on the expression of target genes that are up-regulated by Stat3, AML cell lines were pretreated with 10μM C188-9 for 1 hour, then stimulated with G-CSF (100 ng/mL) for 1 hour, and total RNA was extracted for quantitative RT-PCR. The SOCS3 gene is a Stat3 target gene that encodes the Jak inhibitory protein SOCS3. PIM1 encodes the kinase Pim1, an oncogene implicated in several cancers, including AML,15 which is also an accepted target gene of Stat3.16 The mRNA levels for these transcripts were up-regulated in AML cells on G-CSF treatment, and the increase was reduced in cells that were pretreated with C188-9 (Figure 4A). In contrast, C188-9 did not significantly affect the level of the ATRA-inducible transcript CCL2417 in NB-4 cells stimulated with ATRA. The smaller effect of C188-9 on PIM1 mRNA in Kasumi-1 cells was possibly the result of ERK and/or Akt pathways up-regulating this gene, as has been described.18 Indeed, Figure 3E shows that ERK1/2 and Akt were dramatically activated in Kasumi-1 cells by G-CSF and not inhibited by C188-9. These studies confirm that C188-9 not only inhibited Stat3 activation, it also inhibited Stat3-dependent gene transcription. Reference: Blood. 2011 May 26;117(21):5701-9. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21447830/|
|In vivo activity:||Of the approximately 13,528 discernible genes, levels of 37 gene transcripts are altered by C188 (17 down and 20 up-regulated, fdr <0.01, fold change≥1.5), of which 7 are known STAT3 gene targets. In comparison, C188-9 affects a much greater number of genes involved in oncogenesis (384 total, 95 down- and 289 up-regulated), including 76 genes previously reported as regulated by STAT3 (38 down-regulated and 38 up-regulated). Among the 38 genes previously shown to be upregulated by STAT3, 24 (63%) genes are downregulated by C188-9 treatment, as expected. Additionally, 10 more genes downregulated by C188-9 (fdr <0.01, fold change≥1.5) that previously are shown to be upregulated by STAT1. Thus, 40 of 48 (83.3%) genes downregulated by C188-9 previously are shown to be positively regulated by STAT1, including sixteen genes shown to be co-regulated by STAT3 and STAT1. This analysis raises the possibility that the effect of C188-9 on gene transcript levels in HNSCC tumors is mediated by its effects on both STAT3 and STAT1. Reference: Oncotarget. 2016 May 3;7(18):26307-30. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/27027445/|
|Solvent||Max Conc. mg/mL||Max Conc. mM|
The following data is based on the product molecular weight 471.52 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.
|Concentration / Solvent Volume / Mass||1 mg||5 mg||10 mg|
|1 mM||1.15 mL||5.76 mL||11.51 mL|
|5 mM||0.23 mL||1.15 mL||2.3 mL|
|10 mM||0.12 mL||0.58 mL||1.15 mL|
|50 mM||0.02 mL||0.12 mL||0.23 mL|
|In vitro protocol:||1. Redell MS, Ruiz MJ, Alonzo TA, Gerbing RB, Tweardy DJ. 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. doi: 10.1182/blood-2010-04-280123. Epub 2011 Mar 29. PMID: 21447830; PMCID: PMC3110027.|
|In vivo protocol:||1. Bharadwaj U, Eckols TK, Xu X, Kasembeli MM, Chen Y, Adachi M, Song Y, Mo Q, Lai SY, Tweardy DJ. Small-molecule inhibition of STAT3 in radioresistant head and neck squamous cell carcinoma. Oncotarget. 2016 May 3;7(18):26307-30. doi: 10.18632/oncotarget.8368. Erratum in: Oncotarget. 2019 Feb 22;10(16):1603. PMID: 27027445; PMCID: PMC5041982.|
1: Pedroza M, To S, Assassi S, Wu M, Tweardy D, Agarwal SK. Role of STAT3 in skin fibrosis and transforming growth factor beta signalling. Rheumatology (Oxford). 2017 Sep 23. doi: 10.1093/rheumatology/kex347. [Epub ahead of print] PubMed PMID: 29029263.
2: Akinfenwa PY, Bond WS, Ildefonso CJ, Hurwitz MY, Hurwitz RL. Versican G1 domain enhances adenoviral-mediated transgene expression and can be modulated by inhibitors of the Janus kinase (JAK)/STAT and Src family kinase pathways. J Biol Chem. 2017 Sep 1;292(35):14381-14390. doi: 10.1074/jbc.M116.773549. Epub 2017 Jul 6. PubMed PMID: 28684419; PubMed Central PMCID: PMC5582833.
3: Jung KH, Yoo W, Stevenson HL, Deshpande D, Shen H, Gagea M, Yoo SY, Wang J, Eckols TK, Bharadwaj U, Tweardy DJ, Beretta L. Multifunctional Effects of a Small-Molecule STAT3 Inhibitor on NASH and Hepatocellular Carcinoma in Mice. Clin Cancer Res. 2017 Sep 15;23(18):5537-5546. doi: 10.1158/1078-0432.CCR-16-2253. Epub 2017 May 22. PubMed PMID: 28533225.
4: Gavino AC, Nahmod K, Bharadwaj U, Makedonas G, Tweardy DJ. STAT3 inhibition prevents lung inflammation, remodeling, and accumulation of Th2 and Th17 cells in a murine asthma model. Allergy. 2016 Dec;71(12):1684-1692. doi: 10.1111/all.12937. Epub 2016 Jun 23. PubMed PMID: 27225906.
5: Bharadwaj U, Eckols TK, Xu X, Kasembeli MM, Chen Y, Adachi M, Song Y, Mo Q, Lai SY, Tweardy DJ. Small-molecule inhibition of STAT3 in radioresistant head and neck squamous cell carcinoma. Oncotarget. 2016 May 3;7(18):26307-30. doi: 10.18632/oncotarget.8368. PubMed PMID: 27027445; PubMed Central PMCID: PMC5041982.
6: Lewis KM, Bharadwaj U, Eckols TK, Kolosov M, Kasembeli MM, Fridley C, Siller R, Tweardy DJ. Small-molecule targeting of signal transducer and activator of transcription (STAT) 3 to treat non-small cell lung cancer. Lung Cancer. 2015 Nov;90(2):182-90. doi: 10.1016/j.lungcan.2015.09.014. Epub 2015 Sep 15. PubMed PMID: 26410177; PubMed Central PMCID: PMC4619129.
7: Ellis H. A mass in the right iliac fossa. Br J Hosp Med (Lond). 2012 Dec;73(12):C188-9. PubMed PMID: 23519066.
8: Redell MS, Ruiz MJ, Alonzo TA, Gerbing RB, Tweardy DJ. 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. doi: 10.1182/blood-2010-04-280123. Epub 2011 Mar 29. PubMed PMID: 21447830; PubMed Central PMCID: PMC3110027.
9: Essig A, Wolff D. Sodium flux ratios and electromotive force of sodium transport. Am J Physiol. 1977 Nov;233(5):C188-9. PubMed PMID: 920796.
STAT3 drives development of Th17 cells and cytokine production by Th2 and Th17 cells, which contribute to asthma. Alternative asthma treatments are needed, especially for the Th17 phenotype. inhibition decreases dermal fibrosis in two models of SSc. STAT3 regulates dermal fibroblasts function in vitro and can be activated by TGF-β. These data suggest that STAT3 is a potential therapeutic target for dermal fibrosis in diseases such as SSc.