FLLL32

STAT3 inhibitor CAS# 1226895-15-3

FLLL32

Catalog No. BCC6499----Order now to get a substantial discount!

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Chemical structure

FLLL32

3D structure

Chemical Properties of FLLL32

Cas No. 1226895-15-3 SDF Download SDF
PubChem ID 68019246 Appearance Powder
Formula C28H32O6 M.Wt 464.55
Type of Compound N/A Storage Desiccate at -20°C
Solubility DMSO : 125 mg/mL (269.08 mM; Need ultrasonic)
H2O : < 0.1 mg/mL (insoluble)
Chemical Name (E)-3-(3,4-dimethoxyphenyl)-1-[1-[(E)-3-(3,4-dimethoxyphenyl)prop-2-enoyl]cyclohexyl]prop-2-en-1-one
SMILES COC1=C(C=C(C=C1)C=CC(=O)C2(CCCCC2)C(=O)C=CC3=CC(=C(C=C3)OC)OC)OC
Standard InChIKey NQDROBVIYYEMDQ-WFYKWJGLSA-N
Standard InChI InChI=1S/C28H32O6/c1-31-22-12-8-20(18-24(22)33-3)10-14-26(29)28(16-6-5-7-17-28)27(30)15-11-21-9-13-23(32-2)25(19-21)34-4/h8-15,18-19H,5-7,16-17H2,1-4H3/b14-10+,15-11+
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

FLLL32 Dilution Calculator

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FLLL32 Molarity Calculator

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Preparing Stock Solutions of FLLL32

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.1526 mL 10.7631 mL 21.5262 mL 43.0524 mL 53.8155 mL
5 mM 0.4305 mL 2.1526 mL 4.3052 mL 8.6105 mL 10.7631 mL
10 mM 0.2153 mL 1.0763 mL 2.1526 mL 4.3052 mL 5.3816 mL
50 mM 0.0431 mL 0.2153 mL 0.4305 mL 0.861 mL 1.0763 mL
100 mM 0.0215 mL 0.1076 mL 0.2153 mL 0.4305 mL 0.5382 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on FLLL32

FLLL32 is a small molecule analog of curcumin. It can inhibit signal transducer and activator of transcription-3 (STAT3). In the pSTAT3-positive A375 cell line, FLLL32 resulted in pro-apoptotic effects with an IC50 value of 1.3 μM at 48 hours [1].

Activation of STAT3 in melanoma tumors is related to poor prognosis. STAT3 can promote angiogenesis and cell proliferation, drive invasion and metastasis, and inhibit apoptosis [1].

In multiple human melanoma cell lines, after a 24 hour treatment with FLLL32, the STAT3 phosphorylation at Tyr705 but not at Tyr727 was inhibited. In a prior in vitro cell-free assay, FLLL32 was found to inhibit the activity of Jak2 kinase. But in the experiment with multiple human melanoma cell line, no appreciable alteration in the phosphorylation of Jak2, even when the concentration of FLLL32 was 8 μM, was observed. This meant that FLLL32 likely directly acted against the STAT3 protein. FLLL32 at concentrations ranged from 2-4 μM for only 4 hours reduced pSTAT3 and induce cell death [1].

In an s.c. model of B16F10 melanoma in C57BL/6 mice, compared to the treatment with DMSO to the same animals, daily i.p. administration of FLLL-32 at concentrations of 25 mg/kg and 50 mg/kg significantly delayed tumor growth (p<0.001) [2].

References:
[1].  Bill MA, Fuchs JR, Li C, et al. The small molecule curcumin analog FLLL32 induces apoptosis in melanoma cells via STAT3 inhibition and retains the cellular response to cytokines with anti-tumor activity. Molecular cancer, 2010, 9(1): 165.
[2].  Lesinski G, Bill M, Li C, et al. Abstract# 856: The small molecule curcumin analog FLLL-32 induces apoptosis in human melanoma cells via STAT3 inhibition and elicits in vivo anti-tumor activity. Cancer Research, 2009, 69(9 Supplement): 856-856.

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References on FLLL32

Two small molecule compounds, LLL12 and FLLL32, exhibit potent inhibitory activity on STAT3 in human rhabdomyosarcoma cells.[Pubmed:21109950]

Int J Oncol. 2011 Jan;38(1):279-85.

Signal transducers and activators of transcription 3 (STAT3) signaling is persistently activated in many types of cancer cells, and represents a valid target for anticancer drug design. However, few reports have described the constitutive activation of STAT3 in human sarcoma cells. In this study, we demonstrate that the STAT3 signaling pathway is constitutively activated in human rhabodomyosarcoma cells (RH28, RH30, and RD2). We also investigated the inhibitory effects of two newly developed small molecules, LLL12 and FLLL32, on the STAT3 signaling pathway in human rhabodomyosarcoma cells. Both LLL12 and FLLL32 downregulated STAT3 constitutively and interleukin-6 (IL-6) stimulated phosphorylated STAT3 (p-STAT3). The inhibition of STAT3 via LLL12 and FLLL32 was confirmed by the inhibition of STAT3 DNA binding activity. The downstream targets of STAT3, cyclin D1, Bcl-xL, and survivin were also downregulated by LLL12 and FLLL 32 at both messenger RNA and protein levels. The potency of LLL12 and FLLL32 to inhibit proliferation/viability in human rhabodomyosarcoma cells (RH28, RH30, and RD2) was higher than that of the 5 previously reported Janus kinase 2 (JAK2)/STAT3 inhibitors (LLL3, WP1066, Stattic, S3I-201, and AG490) and curcumin. Thus, in this study, we investigated the inhibitory effects of two STAT3 inhibitors, LLL12 and FLLL32, on the STAT3 signaling pathway in human rhabodomyosarcoma cells; we also demonstrated their higher potency in inhibiting proliferation on human rhabodomyosarcoma cells as compared to other five JAK2/STAT3 inhibitors and curcumin.

The novel curcumin analog FLLL32 decreases STAT3 DNA binding activity and expression, and induces apoptosis in osteosarcoma cell lines.[Pubmed:21443800]

BMC Cancer. 2011 Mar 28;11:112.

BACKGROUND: Curcumin is a naturally occurring phenolic compound shown to have a wide variety of antitumor activities; however, it does not attain sufficient blood levels to do so when ingested. Using structure-based design, a novel compound, FLLL32, was generated from curcumin. FLLL32 possesses superior biochemical properties and more specifically targets STAT3, a transcription factor important in tumor cell survival, proliferation, metastasis, and chemotherapy resistance. In our previous work, we found that several canine and human osteosarcoma (OSA) cell lines, but not normal osteoblasts, exhibit constitutive phosphorylation of STAT3. Compared to curcumin, we hypothesized that FLLL32 would be more efficient at inhibiting STAT3 function in OSA cells and that this would result in enhanced downregulation of STAT3 transcriptional targets and subsequent death of OSA cells. METHODS: Human and canine OSA cells were treated with vehicle, curcumin, or FLLL32 and the effects on proliferation (CyQUANT(R)), apoptosis (SensoLyte(R) Homogeneous AMC Caspase- 3/7 Assay kit, western blotting), STAT3 DNA binding (EMSA), and vascular endothelial growth factor (VEGF), survivin, and matrix metalloproteinase-2 (MMP2) expression (RT-PCR, western blotting) were measured. STAT3 expression was measured by RT-PCR, qRT- PCR, and western blotting. RESULTS: Our data showed that FLLL32 decreased STAT3 DNA binding by EMSA. FLLL32 promoted loss of cell proliferation at lower concentrations than curcumin leading to caspase-3- dependent apoptosis, as evidenced by PARP cleavage and increased caspase 3/7 activity; this could be inhibited by treatment with the pan-caspase inhibitor Z-VAD-FMK. Treatment of OSA cells with FLLL32 decreased expression of survivin, VEGF, and MMP2 at both mRNA and protein levels with concurrent decreases in phosphorylated and total STAT3; this loss of total STAT3 occurred, in part, via the ubiquitin-proteasome pathway. CONCLUSIONS: These data demonstrate that the novel curcumin analog FLLL32 has biologic activity against OSA cell lines through inhibition of STAT3 function and expression. Future work with FLLL32 will define the therapeutic potential of this compound in vivo.

IL-6, a risk factor for hepatocellular carcinoma: FLLL32 inhibits IL-6-induced STAT3 phosphorylation in human hepatocellular cancer cells.[Pubmed:20818158]

Cell Cycle. 2010 Sep 1;9(17):3423-7.

Hepatocellular carcinoma (HCC) is one of the most common human cancers and the patients' five-year survival rate is very low. Growing evidence indicates that interleukin-6 (IL-6) is a risk factor for HCC. High serum IL-6 may promote HCC development in hepatitis B patients. Therefore, IL-6 could be considered a HCC biomarker and blockade of IL-6 pathway may be a promising therapeutic alternative for HCC. STAT3 is major pathway to mediate signal from IL-6 to the nucleus, where different genes associated with proliferation and apoptosis are regulated. We previous reported that IL-6 induces cell survival upon drug treatment in HCC cells and inhibition of IL-6/STAT3 pathway using anti-IL-6 antibody or STAT3 small-molecule inhibitor LLL12 reduces this effect. Here we summarized the recent studies of IL-6 in HCC and showed another STAT3 small-molecule inhibitor FLLL32 also blocked IL-6-induced STAT3 activation in HCC cells. FLLL32 is a novel curcumin analogue, which has been described to suppress the constitutive activation of STAT3 in pancreatic and breast cancer cells in vitro and vivo. We demonstrated that FLLL32 blocked IL-6-induced STAT3 phosphorylation and nuclear translocation.

Small molecules, LLL12 and FLLL32, inhibit STAT3 and exhibit potent growth suppressive activity in osteosarcoma cells and tumor growth in mice.[Pubmed:21340507]

Invest New Drugs. 2012 Jun;30(3):916-26.

Constitutive activation of Signal Transducers and Activators of Transcription 3 (STAT3) is frequently detected in osteosarcoma, and hence, may serve as a therapeutic target. In order to target STAT3, we tested two new STAT3 inhibitors, LLL12 and FLLL32. LLL12 and FLLL32 inhibit STAT3 phosphorylation and STAT3 downstream targets. LLL12 and FLLL32 also inhibit IL-6 induced STAT3 phosphorylation. The inhibition of STAT3 by LLL12 and FLLL32 resulted in the induction of apoptosis, reduction of plating efficiency, and migration in osteosarcoma cells. Furthermore, LLL12 and FLLL32 inhibited SJSA osteosarcoma cells and OS-33 tumor growth in murine xenografts. These results provide evidence that constitutive STAT3 signaling is required for osteosarcoma survival and migration in vitro and tumor growth in vivo. Blocking persistent STAT3 signaling by LLL12 and FLLL32 may be a novel therapeutic approach for osteosarcoma.

Description

FLLL32, a synthetic analog of curcumina, is a JAK2/STAT3 dual inhibitor with anti-tumor activity. FLLL32 can inhibit the induction of STAT3 phosphorylation by IFNα and IL-6 in breast cancer cells.

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