| CAS |
432001-19-9 |
| English Name |
C188-9 |
| Synonyms |
TTI-101 |
| Molecular Formula |
C27H21NO5S |
| Molecular Weight |
471.52 |
| Solubility |
Soluble in DMSO ≥5mg/mL |
| Purity |
≥98% |
| Appearance |
Off-white to brown Solid |
| Storage |
Powder:2-8℃，2 years;Insolvent(Mother Liquid):-20℃，6 months;-80℃，1 year |
| MDL |
MFCD03141581 |
| SMILES |
O=S(C1=CC=C(OC)C=C1)(NC2=C3C=CC=CC3=C(O)C(C4=C5C=CC=CC5=CC=C4O)=C2)=O |
| InChIKey |
QDCJDYWGYVPBDO-UHFFFAOYSA-N |
| InChI |
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 |
| PubChem CID |
1324494 |
| Target Point |
STAT3 |
| Passage |
JAK/STAT Signaling |
| Background |
C188-9 is a novel, potent STAT3 inhibitor |
| Biological Activity |
C188-9 (TTI-101) is a STAT3 inhibitor, with a Kd of 4.7 nM. C188-9 inhibits G-CSF-induced STAT3 activation and STAT3-dependent gene expression. C188-9 induces apoptosis in AML cell lines and primary samples and inhibits colony formation by primary AML blasts[1-4]. |
| In Vitro |
C188-9 is a Stat3 inhibitor，with a Kd of 4.7 nM[1]. The IC50s of C188-9 to inhibit Stat3 activation in AML cell lines are in the range of 4-7 μM，and in primary AML samples the IC50s are in the range of 8-18 μM. For apoptosis studies，AML cell lines and primary samples are treated for 24 hours with C188-9，then apoptotic cells are quantified by FACS analysis for annexin V-labeled cells. The EC50s for apoptosis induction are quite variable，ranging from 6 μM to over 50 μM[2]. |
| In Vivo |
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[3]. |
| 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 |
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]. |
| Data Literature Source |
[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. |
| Unit |
Bottle |
| Specification |
2mg 5mg |
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