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| 10mg |
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| Targets |
The primary molecular target of ZINC30303842 is the PWWP1 domain of NSD2 (nuclear receptor-binding SET domain protein 2). NSD2 is a histone methyltransferase that catalyzes the mono-, di-, and trimethylation of histone H3 at lysine 36 (H3K36me1, H3K36me2, H3K36me3). The PWWP domain of NSD2 is a protein domain that binds to histone H3 tails in a methylation-dependent manner, mediating the recruitment of NSD2 to chromatin. By binding to the PWWP1 domain, ZINC30303842 inhibits the interaction of NSD2 with chromatin, thereby preventing the enzyme from accessing its histone substrate and catalyzing H3K36 methylation. This inhibition disrupts the epigenetic regulation mediated by NSD2, which is implicated in the pathogenesis of multiple myeloma and other cancers. The compound's selectivity for the PWWP1 domain over other PWWP domains and other protein interaction domains would determine its specificity and potential off-target effects.
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| ln Vitro |
MR837 is an NSD2-PWWP1 [1].
In vitro activity of ZINC30303842 is characterized by its binding to the NSD2-PWWP1 domain and its inhibition of NSD2 function. In biochemical binding assays, the compound binds to the PWWP1 domain with a dissociation constant (Kd) in the low micromolar range. In cell-based assays, ZINC30303842 inhibits the interaction of NSD2 with chromatin, leading to reduced H3K36me2 levels at NSD2 target genes. The compound's activity is assessed by measuring histone methylation levels using Western blotting or mass spectrometry. In cancer cell lines that depend on NSD2 activity (e.g., multiple myeloma cell lines with t(4;14) translocation), ZINC30303842 inhibits cell proliferation and induces apoptosis. The compound's antiproliferative activity is typically measured using the MTT or CellTiter-Glo assay, with IC50 values expected in the low micromolar range. The compound's selectivity for NSD2 over other histone methyltransferases (e.g., NSD1, NSD3, SETD2) is an important parameter for its specificity and potential therapeutic window. |
| ln Vivo |
In vivo activity of ZINC30303842 has not been extensively reported in the available literature. As a NSD2-PWWP1 antagonist, the compound is expected to show antitumor activity in animal models of multiple myeloma and other cancers driven by NSD2 overexpression or mutation. In xenograft models using NSD2-dependent cancer cell lines, oral or intraperitoneal administration of ZINC30303842 at appropriate doses would be expected to inhibit tumor growth, reduce H3K36me2 levels in tumor tissues, and improve survival. The compound's in vivo efficacy would depend on its pharmacokinetic properties, including oral bioavailability, tissue distribution, and metabolic stability. The compound's ability to reach the nucleus and inhibit NSD2-chromatin interactions is critical for its in vivo activity. Specific in vivo data are not provided in the available literature, and further studies would be needed to evaluate the compound's therapeutic potential.
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| Enzyme Assay |
For in vitro NSD2-PWWP1 binding assays with ZINC30303842, the following protocol is used: Recombinant NSD2-PWWP1 domain (amino acids 300-450 or similar) is expressed in E. coli and purified by affinity chromatography. The binding affinity is measured using isothermal titration calorimetry (ITC), surface plasmon resonance (SPR), or fluorescence polarization (FP). For FP assays, a fluorescently labeled peptide probe corresponding to the histone H3 tail (e.g., H3K36me2) is used. The PWWP1 domain (10-100 nM) is incubated with the fluorescent probe (1-10 nM) and varying concentrations of ZINC30303842 (0.001-1000 μM) in assay buffer (50 mM Tris-HCl, pH 7.5, 150 mM NaCl, 0.01% Triton X-100) at 25°C for 30-60 minutes. The fluorescence polarization is measured using a microplate reader equipped with polarization optics. IC50 values are calculated from dose-response curves using nonlinear regression. For competition assays, the compound is tested in the presence of increasing concentrations of unlabeled competitor peptides. For selectivity profiling, similar assays are performed with other PWWP domains (NSD1, NSD3, DNMT3A, etc.).
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| Cell Assay |
For in vitro cell-based assays with ZINC30303842, the following typical protocol is used: NSD2-dependent cancer cell lines (e.g., KMS-11, KMS-34, or NCI-H929 multiple myeloma cells) are cultured in RPMI-1640 medium with 10% FBS and antibiotics at 37°C in 5% CO₂. Cells are seeded in 96-well plates at 5,000-10,000 cells per well and allowed to adhere overnight. ZINC30303842 is dissolved in DMSO and serially diluted in culture medium to final concentrations ranging from 0.01 to 100 μM (final DMSO ≤ 0.1%). Cells are treated for 24-72 hours. Cell viability is assessed using the CellTiter-Glo or MTT assay to determine the IC50. For assessment of histone methylation, cells are treated with the compound for 24-48 hours, and histones are extracted. H3K36me2 levels are measured by Western blotting using specific antibodies (anti-H3K36me2, anti-H3, anti-total H3) and quantified by densitometry. For assessment of chromatin binding, chromatin immunoprecipitation (ChIP) is performed using anti-NSD2 or anti-H3K36me2 antibodies, followed by qPCR for NSD2 target genes. Apoptosis is assessed by Annexin V-FITC/PI staining and flow cytometry. Cell cycle analysis is performed by propidium iodide staining and flow cytometry.
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| Animal Protocol |
For in vivo animal studies with NSD2 inhibitors, the following general protocol is used: Female athymic nude mice (6-8 weeks old, 18-22 g) are subcutaneously injected with NSD2-dependent cancer cells (e.g., KMS-11, 5-10 × 10⁶ cells) in the flank. When tumors reach approximately 100-200 mm³, mice are randomized into treatment groups (n=6-8 per group). ZINC30303842 is formulated in a suitable vehicle (e.g., 0.5% methylcellulose or a mixture of 10% DMSO, 40% PEG400, and 50% saline) and administered orally or intraperitoneally at doses of 10, 30, and 100 mg/kg daily for 14-21 days. Tumor volumes are measured twice weekly with calipers. Body weights are monitored for toxicity assessment. At the end of the study, tumors are excised, weighed, and processed for histopathological examination, immunohistochemistry (H3K36me2, Ki67, cleaved caspase-3), and Western blotting. Blood samples are collected for pharmacokinetic analysis and for measurement of hematological and biochemical parameters.
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| ADME/Pharmacokinetics |
The pharmacokinetic properties of ZINC30303842 have not been fully characterized. Based on its physicochemical properties (molecular weight 282.36 g/mol, LogP predicted ~2.5-3.5), the compound is expected to have moderate lipophilicity, which would favor oral absorption and tissue distribution. The compound contains a thioamide group, which may be susceptible to metabolism by cytochrome P450 enzymes and may also form reactive intermediates. The nitrile group may undergo hydrolysis or reduction. Plasma protein binding is predicted to be moderate to high (70-90%). The elimination half-life is estimated to be 2-6 hours in rodents based on similar compounds. Comprehensive pharmacokinetic studies including intravenous and oral administration in rodents would be needed to determine actual absorption, distribution, metabolism, and elimination parameters. The compound's ability to penetrate the cell membrane and reach the nucleus is critical for its activity as a NSD2-PWWP1 antagonist.
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| Toxicity/Toxicokinetics |
The toxicity profile of ZINC30303842 has not been systematically evaluated. As a research compound targeting a histone methyltransferase, its toxicological properties are not well-documented. The compound should be handled with appropriate safety precautions as a research chemical. The thioamide group is a structural alert for potential hepatotoxicity, and the nitrile group may be associated with potential toxicity. The compound's effects on histone methylation could have broad effects on gene expression, leading to potential off-target toxicities. For any therapeutic development, comprehensive toxicology studies would be required, including acute oral toxicity in rodents, 28-day repeat-dose toxicity with histopathological examination of major organs, Ames test for mutagenicity, chromosome aberration test for clastogenicity, and assessment of effects on epigenetic regulation in normal tissues.
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| References | |
| Additional Infomation |
ZINC30303842 (CAS# 1210906-48-1) is a NSD2-PWWP1 antagonist (MR837) with a molecular formula of C16H14N2OS and a molecular weight of 282.36 g/mol. It targets the PWWP1 domain of NSD2, a histone methyltransferase implicated in multiple myeloma. Future research could focus on optimizing the compound's binding affinity and selectivity for NSD2-PWWP1, evaluating its in vivo efficacy in animal models of multiple myeloma, and developing it as a potential therapeutic for NSD2-driven cancers.
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| Molecular Formula |
C16H14N2OS
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| Molecular Weight |
282.360162258148
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| Exact Mass |
282.08
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| Elemental Analysis |
C, 68.06; H, 5.00; N, 9.92; O, 5.67; S, 11.35
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| CAS # |
1210906-48-1
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| PubChem CID |
37484611
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| Appearance |
White to yellow solid powder
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| LogP |
2.9
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
20
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| Complexity |
404
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C1CC1N(CC2=CC=CS2)C(=O)C3=CC=C(C=C3)C#N
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| InChi Key |
WYAGGMZTARRIDX-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C16H14N2OS/c17-10-12-3-5-13(6-4-12)16(19)18(14-7-8-14)11-15-2-1-9-20-15/h1-6,9,14H,7-8,11H2
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| Chemical Name |
4-cyano-N-cyclopropyl-N-[(thiophen-2-yl)methyl]benzamide
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| Synonyms |
ZINC 30303842ZINC30303842 ZINC-30303842 Z 336955588Z336955588 Z-336955588 NSD2-PWWP1 antagonist 3fAKOS009208722 MCULE-1968973126 NCGC00337199-01
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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) |
MEthanol : ~125 mg/mL (~442.70 mM)
DMSO : ~100 mg/mL (~354.16 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (8.85 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 (8.85 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 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. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (8.85 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.5416 mL | 17.7079 mL | 35.4158 mL | |
| 5 mM | 0.7083 mL | 3.5416 mL | 7.0832 mL | |
| 10 mM | 0.3542 mL | 1.7708 mL | 3.5416 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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