P 22077 Chemical Properties

Melting point:

146 - 148°C

Boiling point:

395.4±42.0 °C(Predicted)

Density 

1.53±0.1 g/cm3(Predicted)

storage temp. 

-20°C

solubility 

Soluble in DMSO (up to 25 mg/ml)

form 

solid

color 

Off-white

Stability:

Stable for 1 year from date of purchase as supplied. Solutions in DMSO may be stored at -20°C for up to 3 months.

P 22077 Usage And Synthesis

Description

P22077 (1247819-59-5) is a selective (tested against 23 other DUBs) inhibitor of USP7 (IC50?= 8 μM) and the closely related USP47.1,2?It destabilizes claspin, a scaffolding protein involved in regulating Chk1 kinase, a DNA damage response enzyme.2?P22077 inhibits neuroblastoma growth?via?induction of p53-mediated apoptosis.3?N-Myc was destabilized by P22077 inhibition of USP7 in human neuroblastoma cells.4?It was able to stabilize p53 levels in conjunction with an Mdm2 inhibitor (Nutlin-3,?Cat# 10-1350)?in HCT116 colorectal carcinoma cells.5

Uses

P22077 is an analog of the ubiquitin-specific protease (USP7) inhibitor P5091. It inhibits USP7, as well.

Synthesis

1. 2-Acetyl-5-chlorothiophene (4.00 g, 24.8 mmol) was added in batches to fuming nitric acid (24 mL) cooled in an ice bath. 2. The reaction mixture was stirred at room temperature for 30 minutes and then poured into 200 mL of ice water. 3. The precipitated solid was extracted with ether, and the organic phase was dried, filtered, and concentrated in vacuum to afford the crude product 1-(5-chloro-4-nitrothiophen-2-yl)ethan-1-one (4.50 g, yellow solid), which did not require further purification. 4. 2,4-difluorothiophenol (4.30 g, 29.4 mmol) was added to a solution of sodium methanolate (1.40 g, 26.3 mmol) in methanol (250 mL). 5. The mixture was stirred at room temperature for 20 minutes before the crude product 1-(5-chloro-4-nitrothiophen-2-yl)ethan-1-one (5.50 g) was added. 6. The mixture was stirred overnight and then water (250 mL) was added, the solid formed was collected by filtration and dried under vacuum at 40 °C. The product was reconstituted by acetonitrile over a 2-minute period. 7. The product was recrystallized twice by acetonitrile to give 1-(5-((2,4-difluorophenyl)thio)-4-nitrothiophen-2-yl)ethanone (3.30 g, 39% yield) as a white solid. 8. 1H NMR (300 MHz, DMSO) δ 8.50, 8.00, 7.97, 7.95, 7.9, 7.71, 7.70, 7.68, 7.67, 7.65, 7.64, 7.43, 7.40, 7.37, 2.50.

in vivo

storage

Store at +4°C

References

[1] XUFAN TIAN. Characterization of selective ubiquitin and ubiquitin-like protease inhibitors using a fluorescence-based multiplex assay format.[J]. Assay and drug development technologies, 2011, 9 2: 165-173. DOI:10.1089/adt.2010.0317
[2] MIKAEL ALTUN. Activity-based chemical proteomics accelerates inhibitor development for deubiquitylating enzymes.[J]. Chemistry & biology, 2011: 1401-1412. DOI:10.1016/j.chembiol.2011.08.018
[3] Y-H FAN. USP7 inhibitor P22077 inhibits neuroblastoma growth via inducing p53-mediated apoptosis[J]. Cell Death & Disease, 2013, 4 10: e867-e867. DOI:10.1038/cddis.2013.400
[4] OMID TAVANA. HAUSP deubiquitinates and stabilizes N-Myc in neuroblastoma[J]. Nature Medicine, 2016, 22 10: 1180-1186. DOI:10.1038/nm.4180
[5] OMID TAVANA  Wei G  Hongbin Sun. Targeting HAUSP in both p53 wildtype and p53-mutant tumors.[J]. Cell Cycle, 2018, 17 7: 823-828. DOI:10.1080/15384101.2018.1456293

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