PYZD-4409E1 enzyme inhibitor CAS# 423148-78-1 |
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Quality Control & MSDS
3D structure
Package In Stock
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| Cas No. | 423148-78-1 | SDF | Download SDF |
| PubChem ID | 60111983 | Appearance | Powder |
| Formula | C14H7ClFN3O5 | M.Wt | 351.67 |
| Type of Compound | N/A | Storage | Desiccate at -20°C |
| Solubility | DMSO : ≥ 35 mg/mL (99.53 mM) *"≥" means soluble, but saturation unknown. | ||
| Chemical Name | (4Z)-1-(3-chloro-4-fluorophenyl)-4-[(5-nitrofuran-2-yl)methylidene]pyrazolidine-3,5-dione | ||
| SMILES | C1=CC(=C(C=C1N2C(=O)C(=CC3=CC=C(O3)[N+](=O)[O-])C(=O)N2)Cl)F | ||
| Standard InChIKey | MSYMKEYWUWVZQY-TWGQIWQCSA-N | ||
| Standard InChI | InChI=1S/C14H7ClFN3O5/c15-10-5-7(1-3-11(10)16)18-14(21)9(13(20)17-18)6-8-2-4-12(24-8)19(22)23/h1-6H,(H,17,20)/b9-6- | ||
| General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months. Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it. |
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| About Packaging | 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial. 2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial. 3. Try to avoid loss or contamination during the experiment. |
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| Shipping Condition | Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request. | ||
| Description | Ubiquitin-activating enzyme (E1) inhibitor. Blocks degradation of p53 and cyclin D3. Inhibits NF-κB activation and induces cell death associated with ER stress. Displays antitumor effects in a mouse model of leukemia. |
PYZD-4409 Dilution Calculator
PYZD-4409 Molarity Calculator
| 1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
| 1 mM | 2.8436 mL | 14.2179 mL | 28.4357 mL | 56.8715 mL | 71.0894 mL |
| 5 mM | 0.5687 mL | 2.8436 mL | 5.6871 mL | 11.3743 mL | 14.2179 mL |
| 10 mM | 0.2844 mL | 1.4218 mL | 2.8436 mL | 5.6871 mL | 7.1089 mL |
| 50 mM | 0.0569 mL | 0.2844 mL | 0.5687 mL | 1.1374 mL | 1.4218 mL |
| 100 mM | 0.0284 mL | 0.1422 mL | 0.2844 mL | 0.5687 mL | 0.7109 mL |
| * Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations. | |||||
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PYZD-4409 is a novel small molecule inhibitor of the ubiquitin-activating enzyme E1 with IC50 value of 20μM [1].
The ubiquitin-activating enzyme E1 is involved in the fist step of protein degradation. It uses ATP to adenylate and transfers the ubiquitin molecule to the next enzyme E2. It is demonstrated that the ubiquitination pathway is increased in the primary leukemia cells. Thus, inhibition of E1 can be a target of hematologic malignancies treatment. PYZD-4409 is screened out from a chemical library based on the pyrazolidine pharmacophore. The IC50 value(20μM) of it has been evaluated in a cell-free enzymatic assay. PYZD-4409 can also inhibit E1 in cultured K562 leukemia cells. PYZD-4409 causes cell death in leukemia, myeloma and solid tumor cell lines. In clonogenic growth assays, PYZD-4409 is found to reduce the growth of AML cells over normal hematopoietic cells. As an essential role of protein degradation, the inhibition of E1 resluts in the increased amounts of cyclin D3 and p53 [1].
References:
[1] G. Wei Xu, Mohsin Ali, Tabitha E. Wood et al. The ubiquitin-activating enzyme E1 as a therapeutic target for the treatment of leukemia and multiple myeloma. Blood. 2010, 115(11): 2251-2259.
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The ubiquitin-activating enzyme E1 as a therapeutic target for the treatment of leukemia and multiple myeloma.[Pubmed:20075161]
Blood. 2010 Mar 18;115(11):2251-9.
The proteasomal pathway of protein degradation involves 2 discrete steps: ubiquitination and degradation. Here, we evaluated the effects of inhibiting the ubiquitination pathway at the level of the ubiquitin-activating enzyme UBA1 (E1). By immunoblotting, leukemia cell lines and primary patient samples had increased protein ubiquitination. Therefore, we examined the effects of genetic and chemical inhibition of the E1 enzyme. Knockdown of E1 decreased the abundance of ubiquitinated proteins in leukemia and myeloma cells and induced cell death. To further investigate effects of E1 inhibition in malignancy, we discovered a novel small molecule inhibitor, 3,5-dioxopyrazolidine compound, 1-(3-chloro-4-fluorophenyl)-4-[(5-nitro-2-furyl)methylene]-3,5-pyrazolidinedione (PYZD-4409). PYZD-4409 induced cell death in malignant cells and preferentially inhibited the clonogenic growth of primary acute myeloid leukemia cells compared with normal hematopoietic cells. Mechanistically, genetic or chemical inhibition of E1 increased expression of E1 stress markers. Moreover, BI-1 overexpression blocked cell death after E1 inhibition, suggesting ER stress is functionally important for cell death after E1 inhibition. Finally, in a mouse model of leukemia, intraperitoneal administration of PYZD-4409 decreased tumor weight and volume compared with control without untoward toxicity. Thus, our work highlights the E1 enzyme as a novel target for the treatment of hematologic malignancies.
