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| Targets |
ZLDI-8 targets ADAM-17 (a disintegrin and metalloproteinase 17), also known as TACE (TNF-α converting enzyme). ADAM-17 is responsible for the cleavage and activation of Notch protein, a key regulator of cell fate determination, proliferation, and apoptosis. By inhibiting ADAM-17, ZLDI-8 prevents Notch cleavage and activation. The compound also targets Lyp (tyrosine phosphatase) as a competitive and irreversible inhibitor with an IC₅₀ of 31.6 μM and a Ki of 26.22 μM. By inhibiting these targets, ZLDI-8 decreases the expression of pro-survival/anti-apoptosis and EMT-related proteins, making it a valuable tool for cancer research.
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| ln Vitro |
ZLDI-8 (0.03-30 μM; 6-72 hours; MHCC97-H cells) treatment decreases cell viability in a dose- and time-dependent manner [1]. ZLDI-8 (1-10 μM; 6-72 hours; MHCC97-H cells) dramatically decreased the amount of NICDs present and their accumulation in the nucleus. ZLDI-8 also inhibits the expression of cIAP1/2 and Survivin, two pro-survival/anti-apoptotic regulators. Moreover, it decreases the expression of the mesenchymal markers Vimentin and N-Cadherin and increases the expression of the epithelial marker E-Cadherin [1]. By inhibiting the Notch pathway and preventing chemoresistance, ZLDI-8 increases the impact of chemotherapy on tumor cell proliferation, induction of apoptosis, and cell cycle arrest [1].
In vitro, ZLDI-8 inhibits Notch activating/cleaving enzyme ADAM-17 and inhibits the cleavage of Notch protein. The compound decreases the expression of pro-survival/anti-apoptosis and epithelial-mesenchymal transition (EMT) related proteins. It is also a competitive and irreversible tyrosine phosphatase (Lyp) inhibitor with an IC₅₀ of 31.6 μM and a Ki of 26.22 μM. ZLDI-8 inhibits the growth of MHCC97-H cells with an IC₅₀ of 5.32 μM. The compound's multiple inhibitory activities make it a valuable tool for studying Notch signaling, EMT, and cancer cell growth. |
| ln Vivo |
In tumor-bearing nude animal models, ZLDI-8 (0.2-2 mg/kg; intraperitoneal injection; every two days; 20 consecutive days; nude mice) treatment improved sorafenib's inhibitory effect on tumor growth [1].
In vivo, ZLDI-8 has potential applications in cancer therapy based on its inhibition of ADAM-17 and Notch cleavage. Notch signaling is involved in tumor progression, EMT, and drug resistance. By inhibiting Notch activation and decreasing pro-survival/anti-apoptosis and EMT-related proteins, ZLDI-8 may suppress tumor growth and metastasis. The compound's tyrosine phosphatase inhibitory activity may further contribute to its anticancer effects. However, detailed in vivo efficacy, pharmacokinetic, and toxicological data for ZLDI-8 require further investigation from primary research publications. The compound is supplied as a research chemical for preclinical studies. |
| Enzyme Assay |
In vitro enzyme/receptor binding (non-cellular) assays for ZLDI-8 involve measuring inhibition of ADAM-17 and Lyp activities. For ADAM-17 assays, purified enzyme is incubated with a fluorogenic peptide substrate and varying concentrations of ZLDI-8. Cleavage of the substrate releases a fluorescent signal that is monitored over time. IC₅₀ values are calculated from concentration-response curves. For Lyp (tyrosine phosphatase) assays, the enzyme is incubated with a phosphopeptide substrate and varying concentrations of the compound. Phosphate release is measured using colorimetric or fluorometric methods. The compound shows competitive and irreversible inhibition with an IC₅₀ of 31.6 μM and a Ki of 26.22 μM. These assays help characterize the compound's mechanism of action and potency against its targets.
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| Cell Assay |
Cell viability assay[1]
Cell Types: MHCC97-H Cell Tested Concentrations: 0.03 μM, 0.1 μM, 0.3 μM, 1 μM, 3 μM, 10 μM, 30 μM Incubation Duration: 6 hrs (hours), 12 hrs (hours), 24 hrs (hours), 48 hrs (hours), 72-hour Experimental Results: Cytotoxic effects on MHCC97-H cells in a time- and dose-dependent manner. Western Blot Analysis[1] Cell Types: MHCC97-H Cell Tested Concentrations: 1 μM, 3 μM, 10 μM Incubation Duration: 6 hrs (hours), 12 hrs (hours), 24 hrs (hours), 48 hrs (hours), 72 hrs (hours) Experimental Results: NICD levels were Dramatically diminished, NICD was accumulate in the cell nucleus. Also diminished the expression of pro-survival/anti-apoptotic regulators Survivin and cIAP1/2 In vitro cellular experiments with ZLDI-8 are performed using MHCC97-H hepatocellular carcinoma cells or other cancer cell lines. Cells are cultured in appropriate media (e.g., DMEM with 10% FBS) and treated with varying concentrations of ZLDI-8 (typically 0.1-50 μM) for 24-72 hours. Cell viability and proliferation are assessed using MTT or CellTiter-Glo assays. The compound shows an IC₅₀ of 5.32 μM for growth inhibition. Notch signaling and EMT markers are assessed by Western blot analysis using antibodies against Notch, its downstream targets, and EMT-related proteins (E-cadherin, N-cadherin, vimentin). Apoptosis is evaluated by Annexin V/PI staining and flow cytometry. Cells are maintained at 37°C in 5% CO₂ with appropriate media supplements. |
| Animal Protocol |
Animal/Disease Models: MHCC-97H cell nude mice [1]
Doses: 2 mg/kg, 1 mg/kg, 500 μg/kg, 200 μg/kg Route of Administration: intraperitoneal (ip) injection; every two days; 20 days Experimental Results: Inhibition Tumor growth in a nude mouse model of HCC. In vivo animal studies with ZLDI-8 have not been extensively reported. For hepatocellular carcinoma research, standard in vivo models include xenografts of MHCC97-H or other liver cancer cell lines in immunocompromised mice. Mice are injected with cancer cells via subcutaneous or orthotopic implantation, and after tumor establishment, treated with ZLDI-8 via oral, intraperitoneal, or intravenous administration at various doses and schedules. Efficacy is assessed by measuring tumor volume, weight, metastasis, and survival. Pharmacodynamic markers such as Notch activation, EMT markers, and apoptosis markers in tumor tissues may be measured to confirm target engagement. Further studies are needed to establish in vivo efficacy and safety. |
| ADME/Pharmacokinetics |
Pharmacokinetic properties of ZLDI-8 are not extensively characterized. The compound has molecular formula C₂₄H₂₃N₃O₃S and molecular weight 433.52 g/mol. Purity: 98%. As a small molecule (molecular weight 433.52), it is expected to have reasonable oral bioavailability and cellular permeability. Storage: follow manufacturer's guidelines. Detailed pharmacokinetic parameters including half-life, clearance, and bioavailability require further investigation from primary research publications. The compound is supplied as a research chemical for preclinical studies.
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| Toxicity/Toxicokinetics |
Toxicological information for ZLDI-8 is not extensively detailed in the available literature. As a research compound with multi-target inhibitory activity, it should be handled with appropriate safety precautions. Standard safety guidelines for handling potent pharmaceutical compounds apply, including use of personal protective equipment (gloves, safety goggles, lab coat) and working in a well-ventilated area. The compound is intended for research use only and is not approved for human therapeutic use. Cytotoxicity studies in cell-based assays help establish the therapeutic window and selectivity index of the compound.
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| References |
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| Additional Infomation |
ZLDI-8 (CAS 667880-38-8) is a Notch activating/cleaving enzyme ADAM-17 inhibitor that inhibits the cleavage of Notch protein. The compound has molecular formula C₂₄H₂₃N₃O₃S and molecular weight 433.52 g/mol. ZLDI-8 decreases the expression of pro-survival/anti-apoptosis and EMT-related proteins. It is also a competitive and irreversible tyrosine phosphatase (Lyp) inhibitor with an IC₅₀ of 31.6 μM and a Ki of 26.22 μM. The compound inhibits MHCC97-H cell growth with an IC₅₀ of 5.32 μM. Purity: 98%.
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| Molecular Formula |
C₂₄H₂₃N₃O₃S
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| Molecular Weight |
433.52
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| Exact Mass |
433.146
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| Elemental Analysis |
C, 66.49; H, 5.35; N, 9.69; O, 11.07; S, 7.40
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| CAS # |
667880-38-8
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| PubChem CID |
989566
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| Appearance |
Yellow to orange solid powder
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| Density |
1.3±0.1 g/cm3
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| Index of Refraction |
1.662
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| LogP |
5.26
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
31
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| Complexity |
732
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| Defined Atom Stereocenter Count |
0
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| SMILES |
S=C1N([H])C(/C(/C(N1[H])=O)=C(/[H])\C1C2=C([H])C([H])=C([H])C([H])=C2N(C([H])([H])C([H])([H])OC2C([H])=C([H])C(C([H])([H])[H])=C([H])C=2C([H])([H])[H])C=1C([H])([H])[H])=O
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| InChi Key |
GNBZGGYWSRGVBG-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C24H23N3O3S/c1-14-8-9-21(15(2)12-14)30-11-10-27-16(3)18(17-6-4-5-7-20(17)27)13-19-22(28)25-24(31)26-23(19)29/h4-9,12-13H,10-11H2,1-3H3,(H2,25,26,28,29,31)
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| Chemical Name |
5-[[1-[2-(2,4-dimethylphenoxy)ethyl]-2-methylindol-3-yl]methylidene]-2-sulfanylidene-1,3-diazinane-4,6-dione
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| Synonyms |
ZLDI8; ZLDI 8
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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 : ~62.5 mg/mL (~144.17 mM)
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3067 mL | 11.5335 mL | 23.0670 mL | |
| 5 mM | 0.4613 mL | 2.3067 mL | 4.6134 mL | |
| 10 mM | 0.2307 mL | 1.1533 mL | 2.3067 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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