PYZD-4409

E1 enzyme inhibitor CAS# 423148-78-1

PYZD-4409

Catalog No. BCC4253----Order now to get a substantial discount!

Product Name & Size Price Stock
PYZD-4409: 5mg $115 In Stock
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Chemical structure

PYZD-4409

3D structure

Chemical Properties of PYZD-4409

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.
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.
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.

Biological Activity of PYZD-4409

DescriptionUbiquitin-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

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PYZD-4409 Molarity Calculator

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Preparing Stock Solutions of PYZD-4409

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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Background on PYZD-4409

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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References on PYZD-4409

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.

Description

PYZD-4409 is a specific inhibitor of the ubiquitin-activating enzyme UBA1 with an IC50 of 20 μM (cell-free enzymatic assay). PYZD-4409 induces cell death in malignant cells and preferentially inhibits the clonogenic growth of primary acute myeloid leukemia cells.

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