| Size | Price | |
|---|---|---|
| 500mg | ||
| 1g | ||
| Other Sizes |
| Targets |
WDR5 (WD40 repeat protein 5) - binds to the peptide-binding cleft (WIN site) of WDR5. Kdis (displacement constant) for compound 47 = 0.27 ± 0.06 μM. [1]
|
|---|---|
| ln Vitro |
- Compound 47 displaced a fluorescein-labeled H3(1-15) peptide (ARTKQTARKSTGGKA) from its binding pocket in WDR5 in a fluorescence polarization (FP) assay, with a Kdis value of 0.27 ± 0.06 μM. This represents a greater than 25-fold gain in potency compared to the parent compound 2 (Kdis = 6.9 ± 1.5 μM). [1]
- X-ray crystallography (PDB code 4IA9) revealed that compound 47 occupies the central cavity of WDR5. It forms direct and water-mediated hydrogen bonds with S91 and C261, respectively. The 3-methyl and 4-fluoro substituents on the 2-chlorophenyl moiety bring hydrophobic interactions with side-chains lining the binding pocket. The nitro group occupies a hydrophobic cleft that is occluded in most WDR5 structures, involving opening-up of a cavity and aromatic stacking with F133. [1] |
| Enzyme Assay |
- Fluorescence Polarization (FP) Assay: The assay detects displacement of a fluorescein-labeled H3(1-15) peptide (ARTKQTARKSTGGKA) from its binding pocket in WDR5. Binding of the labeled peptide to WDR5 (KD = 458 ± 45 nM) increases the FP signal. Test compounds compete with and displace the labeled peptide, resulting in a reduction of signal. By monitoring the change in FP signal upon varying the concentration of compounds, Kdisplacement (Kdis) values were calculated by fitting the data to a hyperbolic function. This assay was used to evaluate all compounds in Tables 1, 2, and 3. [1]
- Protein Crystallography: WDR5 was purified and co-crystallized with compound 47. The crystal structure of the WDR5-47 complex was determined at high resolution (PDB code 4IA9). The structure showed that compound 47 occupies the central cavity of WDR5, recapitulating interactions previously observed with less potent analogs, including direct and water-mediated hydrogen bonds with S91 and C261, opening-up of a cavity occupied by the nitro group, and aromatic stacking with F133. The 3-methyl and 4-fluoro substituents bring hydrophobic interactions with side-chains lining the binding pocket. [1] |
| References | |
| Additional Infomation |
- Compound 47 was synthesized via a two-step sequence: (1) reaction of 2-fluoro-5-nitroaniline with 2-chloro-3-methyl-4-fluorobenzoyl chloride, followed by (2) displacement of the fluorine with N-methylpiperazine. [1]
- The compound binds to the WIN site of WDR5, which normally accommodates an arginine side chain of interacting peptides (e.g., MLL1 WIN motif). Antagonism of the WDR5-MLL interaction is proposed as a strategy to inhibit MLL complex activity, which is implicated in various cancers, including MLL-rearranged leukemias. [1] - The structure-activity relationship (SAR) study revealed that the N-methylpiperazine moiety is critical for activity, with modifications (demethylation, replacement, ring expansion/contraction) generally leading to loss of potency. The 2-chloro-3-methyl-4-fluorophenyl substitution at the benzamide moiety provided the best potency (25-fold improvement over parent compound 2). Variations at the C-5 position (nitro group) generally produced inactive compounds, although larger aromatic groups (2-furan, 4-pyridine) allowed for modest 2-3 fold potency increases. [1] |
| Molecular Formula |
C19H20CLFN4O3
|
|---|---|
| Molecular Weight |
406.84
|
| CAS # |
1422389-91-0
|
| Appearance |
Typically exists as solids at room temperature
|
| Density |
1.374±0.06 g/cm3(Predicted)
|
| Boiling Point |
500.9±50.0 °C(Predicted)
|
| LogP |
0
|
| SMILES |
C(NC1=CC([N+]([O-])=O)=CC=C1N1CCN(C)CC1)(=O)C1=CC=C(F)C(C)=C1Cl
|
| Synonyms |
WDR5-47; 1422389-91-0; WDR-5-47; 2-Chloro-4-fluoro-3-methyl-N-(2-(4-methylpiperazin-1-yl)-5-nitrophenyl)benzamide; WDR5-47; CHEMBL2337032; 2-Chloro-4-Fluoro-3-Methyl-N-[2-(4-Methylpiperazin-1-Yl)-5-Nitrophenyl]benzamide;
|
| HS Tariff Code |
2934.99.9001
|
| 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)
|
| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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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 | 2.4580 mL | 12.2898 mL | 24.5797 mL | |
| 5 mM | 0.4916 mL | 2.4580 mL | 4.9159 mL | |
| 10 mM | 0.2458 mL | 1.2290 mL | 2.4580 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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