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| Targets |
S-3304 targets matrix metalloproteinases (MMPs), specifically MMP-2 and MMP-9. It inhibits MMP-2 with an IC50 of 2 nM and MMP-9 with an IC50 of 10–16 nM. It shows no significant inhibition of MMP-1 (IC50 = 19 μM), MMP-3 (IC50 = 20 nM), or MMP-7, thus offering a favorable selectivity profile that reduces toxicity. This selectivity is critical for its therapeutic potential in cancer.
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| ln Vitro |
S-3304 is a new derivative of tryptophan and a strong, non-cytotoxic, oral matrix metalloproteinase inhibitor (MMPI). According to biochemical investigations, S 3304 most potently inhibits MMP-2 and MMP-9 activity, but not MMP-1, MMP-3, or MMP-7. As a result, it might not have the musculoskeletal side effects associated with non-specific inhibitors. 1].
S-3304 is a potent inhibitor of MMP-2 (IC50 = 2 nM) and MMP-9 (IC50 = 10–16 nM). It is noncytotoxic to normal cells and does not inhibit MMP-1, MMP-3, or MMP-7. The compound effectively inhibits tumor cell invasion and migration in vitro and disrupts extracellular matrix degradation, which is essential for tumor progression and metastasis. |
| ln Vivo |
Oral administration of S 3304 at doses ranging from 20 to 200 mg/kg suppresses angiogenesis artificially produced in mice by the dorsal air bag method, according to in vivo pharmacology studies. Comparable oral dosages of S 3304 were successful in preventing the liver metastasis of C-1H human colon cancer implanted in the spleen and the lung metastatic colonization of Lewis mouse lung cancer injected via tail vein [1].
S-3304 prolongs survival in murine xenograft models of cancer. In healthy volunteers, it is well tolerated at doses up to 3200 mg twice daily, with no significant adverse events. In Phase I trials in patients with advanced solid tumors, it demonstrated safety and tolerability, and showed signs of biological activity by reducing MMP-9 levels in plasma. Further clinical development has been explored. |
| Enzyme Assay |
The in vitro activity of S-3304 is assessed using enzyme inhibition assays with purified recombinant human MMPs. The compound is incubated with the enzyme and a fluorogenic peptide substrate, and the cleavage product is measured fluorometrically. IC50 values are calculated from dose-response curves for MMP-2, MMP-9, and other MMPs to confirm selectivity.
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| Cell Assay |
Cell-based assays evaluate S-3304's ability to inhibit cancer cell invasion and migration. Using Matrigel invasion chambers, cancer cell lines (e.g., HT1080 fibrosarcoma) are treated with S-3304, and the number of cells invading through the membrane is counted. Gelatin zymography is used to measure MMP-2 and MMP-9 activity in conditioned media from treated cells, confirming target engagement.
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| Animal Protocol |
S-3304 has been evaluated in murine xenograft models of human tumors. Tumor-bearing mice are treated orally with S-3304 at various doses, and tumor growth, metastasis, and survival are monitored. In healthy volunteer studies, single and multiple ascending doses (up to 3200 mg twice daily) were administered to assess safety, tolerability, and pharmacokinetics. Phase I trials in cancer patients also evaluated its pharmacodynamic effects.
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| ADME/Pharmacokinetics |
S-3304 has a molecular weight of 464.6 and a molecular formula of C24H20N2O4S2. The IUPAC name is (2R)-3-(1H-indol-3-yl)-2-[[5-[2-(4-methylphenyl)ethynyl]thiophen-2-yl]sulfonylamino]propanoic acid. It is soluble in DMSO and should be stored at -20°C, protected from light. Purity is typically ≥97% by HPLC. The compound is an orally available MMP inhibitor.
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| Toxicity/Toxicokinetics |
S-3304 is a research compound that has been evaluated in clinical trials and shown to be safe and well tolerated. In healthy volunteers, no dose-limiting toxicities were observed up to 3200 mg twice daily. It lacks the musculoskeletal side effects (e.g., tendinopathy) associated with broad-spectrum MMP inhibitors, likely due to its selectivity for MMP-2 and MMP-9. Standard safety precautions should be followed in research settings.
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| References | |
| Additional Infomation |
S-3304 has been used in therapeutic trials for various cancers, including lung cancer, solid tumors, non-small cell lung cancer (NSCLC), stage IIIB NSCLC, and stage IIIA NSCLC. The MMP inhibitor S-3304 is an oral medication with potential antitumor activity. S-3304 inhibits matrix metalloproteinases (MMPs), thereby inducing extracellular matrix degradation and inhibiting angiogenesis, tumor growth, invasion, and metastasis. (NCI04)
S-3304 (CAS#: 203640-27-1) is a potent, orally active, noncytotoxic inhibitor of MMP-2 (IC50 = 2 nM) and MMP-9 (IC50 = 10–16 nM), with high selectivity over other MMPs. It is a D-tryptophan derivative that inhibits angiogenesis, tumor invasion, and metastasis. S-3304 has been studied in Phase I trials for advanced solid tumors and is well tolerated with no musculoskeletal toxicity. It is a valuable research tool for studying MMP biology and cancer therapeutics. |
| Molecular Formula |
C24H20N2O4S2
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|---|---|
| Molecular Weight |
464.55
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| Exact Mass |
464.086
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| CAS # |
203640-27-1
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| PubChem CID |
10718956
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
5.383
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
32
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| Complexity |
835
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| Defined Atom Stereocenter Count |
1
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| SMILES |
CC1=CC=C(C=C1)C#CC2=CC=C(S2)S(=O)(=O)N[C@H](CC3=CNC4=CC=CC=C43)C(=O)O
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| InChi Key |
YWCLDDLVLSQGSZ-JOCHJYFZSA-N
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| InChi Code |
InChI=1S/C24H20N2O4S2/c1-16-6-8-17(9-7-16)10-11-19-12-13-23(31-19)32(29,30)26-22(24(27)28)14-18-15-25-21-5-3-2-4-20(18)21/h2-9,12-13,15,22,25-26H,14H2,1H3,(H,27,28)/t22-/m1/s1
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| Chemical Name |
(2R)-3-(1H-indol-3-yl)-2-[[5-[2-(4-methylphenyl)ethynyl]thiophen-2-yl]sulfonylamino]propanoic acid
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| Synonyms |
S3304; S 3304; S-3304
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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 : ≥ 83.3 mg/mL (~179.31 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.38 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 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 25.0 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: 2.5 mg/mL (5.38 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline 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 | 2.1526 mL | 10.7631 mL | 21.5262 mL | |
| 5 mM | 0.4305 mL | 2.1526 mL | 4.3052 mL | |
| 10 mM | 0.2153 mL | 1.0763 mL | 2.1526 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.
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