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| Targets |
SHP-1 p-STAT3
SC-43 targets SHP-1 (PTPN6), a protein tyrosine phosphatase that serves as a negative regulator of the STAT3 signaling pathway. By binding to the N-SH2 domain of SHP-1 and relieving its autoinhibitory conformation, SC-43 activates SHP-1 phosphatase activity. This activation leads to the dephosphorylation and inactivation of STAT3, thereby suppressing STAT3-dependent transcription of genes involved in cell proliferation, survival, and tumorigenesis. |
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| ln Vitro |
Treatment with SC-43 (0-10 μM; 24 hours) enhanced sub-G1 cells and G2-M arrest in HuCCT-1, KKU-100, and CGCCA cells, suggesting that SC-43 promotes specific apoptosis in these cell lines Function[1]. The HuCCT-1, KKU-100, and CGCCA cells treated with SC-43 (0-10 μM) for 24 hours demonstrated a considerable rise in cleaved caspase-3 and PARP levels [1]. By stimulating SH2 domain-containing phosphatase 1 (SHP-1) activity, SC-43 causes p-STAT3 to be downregulated, which in turn causes cyclin B1 and Cdc2 to be downstream. By directly attaching to N-SH2 and removing its own inhibition, SC-43 increases SHP-1 activity [1].
SC-43 exhibits potent anti-proliferative activity in cholangiocarcinoma (CCA) cell lines by inhibiting STAT3 phosphorylation and inducing cell apoptosis. It activates SHP-1 through binding to its N-SH2 domain, relieving autoinhibition. This results in downstream downregulation of cyclin B1 and Cdc2, key regulators of cell cycle progression. The compound's ability to inhibit STAT3 phosphorylation and promote apoptosis has been demonstrated in various cancer cell models. |
| ln Vivo |
Treatment with SC-43 (10-30 mg/kg; gavage; daily; for 23 days; male NCr athymic nude mice) inhibited the formation of xenograft tumors, decreased p-STAT3, and elevated SHP-1 activity[1].
In animal studies, SC-43 inhibits xenograft tumor growth, reduces p-STAT3 levels, and elevates SHP-1 activity. These findings suggest that SC-43 has potential as an anti-fibrotic and anticancer agent, particularly in cholangiocarcinoma. The compound's oral activity makes it suitable for in vivo administration. Further research is needed to fully explore its therapeutic applications in various disease models, including liver fibrosis and other cancers where STAT3 signaling is dysregulated. |
| Enzyme Assay |
The in vitro enzyme/receptor binding (cell-free) assay for SC-43 typically involves a SHP-1 phosphatase activity assay using a synthetic phosphopeptide substrate. Recombinant SHP-1 protein is incubated with varying concentrations of SC-43, and the release of phosphate from the substrate is measured using a colorimetric or fluorometric detection method. The increase in phosphatase activity indicates SHP-1 activation by the compound. Alternatively, a binding assay can be performed to measure SC-43's interaction with the N-SH2 domain of SHP-1 using surface plasmon resonance or isothermal titration calorimetry.
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| Cell Assay |
Cell Viability Assay[1]
Cell Types: HuCCT-1, KKU-100, and CGCCA cells Tested Tested Concentrations: 0 μM, 0.25 μM, 0.5 μM, 0.75 μM, 1 μM, 2.5 μM, 5 μM, 10 μM Incubation Duration: 24 hrs (hours) , 48 hrs (hours), 72 hrs (hours) Experimental Results: Revealed the anti-proliferative effects in CCA cell lines in a dose-dependent manner after treating 24, 48 and 72 hrs (hours) respectively. Cell Cycle Analysis[1] Cell Types: HuCCT-1, KKU-100 , and CGCCA cells Tested Tested Concentrations: 0 μM, 1 μM, 2.5 μM, 5 μM, 10 μM Incubation Duration: 24 hrs (hours) Experimental Results: demonstrated increased sub-G1 cells and G2-M arrest. Western Blot Analysis[1] Cell Types: HuCCT- 1, KKU-100, and CGCCA cells Tested Tested Concentrations: 0 μM, 1 μM, 2.5 μM, 5 μM, 10 μM Incubation Duration: 24 hrs (hours) Experimental Results: Demonstrated significant increase in cleaved caspase-3 and PARP level. The in vitro cellular assay for SC-43 typically uses cholangiocarcinoma (CCA) cell lines, where the compound's effects on STAT3 phosphorylation, cell apoptosis, and proliferation are assessed. Cells are treated with varying concentrations of SC-43, followed by Western blot analysis to measure p-STAT3, total STAT3, and apoptosis markers such as cleaved PARP and caspase-3. Cell viability is measured using MTT or CellTiter-Glo assays. Cyclin B1 and Cdc2 levels can also be evaluated to confirm downstream pathway modulation. |
| Animal Protocol |
Animal/Disease Models: Male NCr athymic nude mice (5-7 weeks of age) injected with HuCCT-1 cells[1]
Doses: 10 mg/kg or 30 mg/kg Route of Administration: Oral gavage; daily; for 23 days Experimental Results: demonstrated xenograft tumor growth inhibition, p-STAT3 reduction and SHP-1 activity elevation. In vivo animal studies for SC-43 typically involve xenograft tumor models in immunodeficient mice, where the compound's anti-tumor efficacy is evaluated. Mice bearing subcutaneous tumors derived from cholangiocarcinoma or other cancer cell lines are treated with SC-43 via oral administration at various doses. Tumor growth inhibition is monitored over time, and at study endpoint, tumors are harvested for analysis of p-STAT3 levels, SHP-1 activity, and apoptosis markers. The compound's effect on liver fibrosis can also be assessed in relevant animal models. |
| ADME/Pharmacokinetics |
SC-43 is an orally active compound with favorable pharmacokinetic properties. As a Sorafenib derivative, it is designed for oral bioavailability. Detailed pharmacokinetic parameters, including absorption, distribution, metabolism, and excretion profiles, are not extensively reported in the available literature. The compound's oral activity has been demonstrated through its efficacy in animal models. Researchers should consult the primary literature for specific PK data if needed for their studies.
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| Toxicity/Toxicokinetics |
Toxicity data for SC-43 are not extensively reported in the public domain. As a research compound, comprehensive toxicological evaluations have not been performed. Standard safety precautions should be taken when handling this compound, including the use of appropriate personal protective equipment. The compound is intended for laboratory research use only and should not be used for human consumption. Refer to the Material Safety Data Sheet for specific safety and handling information.
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| References | |
| Additional Infomation |
SHP-1 agonist SC-43 is an orally administered small molecule agonist that activates phosphatase-1 (SHP-1; tyrosine protein phosphatase non-receptor type 6; PTPN6) containing the Src homology 2 domain, exhibiting potential antitumor activity. After administration, SC-43 enhances SHP-1 activity by disrupting the binding between the N-terminal Src homology 2 (N-SH2) domain and the protein tyrosine phosphatase (PTP) domain, thereby triggering a conformational change in SHP-1 and relieving its autoinhibition. SHP-1 activation inhibits the signal transduction and activator of transcription 3 (STAT3) signaling pathway by suppressing constitutive and interleukin-6 (IL-6)-induced STAT3 phosphorylation. The STAT3 pathway is overactive in many cancer types and is associated with cancer stem cell-mediated growth, recurrence, stemness, and resistance to conventional chemotherapy.
SC-43 is a potent, orally active SHP-1 agonist that inhibits STAT3 phosphorylation and induces apoptosis. As a Sorafenib derivative, it exhibits anti-fibrotic and anticancer effects. Its mechanism involves binding to the N-SH2 domain of SHP-1, relieving autoinhibition and activating the phosphatase to dephosphorylate STAT3. SC-43 has shown efficacy in cholangiocarcinoma cell lines and xenograft models. It is not in clinical trials and has not been approved for therapeutic use. It remains a research tool for studying SHP-1-STAT3 signaling. |
| Molecular Formula |
C21H13CLF3N3O2
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|---|---|
| Molecular Weight |
431.80
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| Exact Mass |
431.064
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| CAS # |
1400989-25-4
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| PubChem CID |
70688629
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| Appearance |
White to off-white solid powder
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| LogP |
6
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
30
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| Complexity |
631
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C(F)(F)(C1C=C(C=CC=1Cl)NC(=O)NC1=CC(=CC=C1)OC1=CC=C(C=C1)C#N)F
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| InChi Key |
QIBWSQJZKMUZAK-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C21H13ClF3N3O2/c22-19-9-6-15(11-18(19)21(23,24)25)28-20(29)27-14-2-1-3-17(10-14)30-16-7-4-13(12-26)5-8-16/h1-11H,(H2,27,28,29)
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| Chemical Name |
1-[4-chloro-3-(trifluoromethyl)phenyl]-3-[3-(4-cyanophenoxy)phenyl]urea
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| 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) |
DMSO: 250 mg/mL (578.97 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.08 mg/mL (4.82 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
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. Solubility in Formulation 2: ≥ 2.08 mg/mL (4.82 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3159 mL | 11.5794 mL | 23.1589 mL | |
| 5 mM | 0.4632 mL | 2.3159 mL | 4.6318 mL | |
| 10 mM | 0.2316 mL | 1.1579 mL | 2.3159 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.
Link: https://clinicaltrials.gov/ct2/show/NCT04733521
Conditions:Advanced Non-small-cell Lung Cancer|Advanced Biliary Tract CancerLink: https://clinicaltrials.gov/ct2/show/NCT03443622
Conditions:Refractory Solid TumorProducts are for research use only; We do not sell to patients
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