PYR-41
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MedKoo CAT#: 406481

CAS#: 418805-02-4

Description: PYR-41 is a ubiquitin-activating enzyme inhibitor (UBE1 inhibitor). PYR-41 blocks ubiquitination reactions but paradoxically leads to the accumulation of high MW ubiquitinated proteins. PYR-41 also mediated cross-linking of specific protein kinases (Bcr-Abl, Jak2) to inhibit their signaling activity. PYR-41 has demonstrated anti-tumor activity in animal studies, partially selective protein cross-linking may represent an alternate approach to affect signal transduction modules and ubiquitin cycle-regulatory proteins for cancer therapy. (Biochem Pharmacol. 2011 Aug 15;82(4):341-9.) (Note: PYR-41 in solution may exist as a mixture of E- and Z- isomers. HPLC may show two peaks depending on conditions).


Chemical Structure

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PYR-41
CAS# 418805-02-4

Theoretical Analysis

MedKoo Cat#: 406481
Name: PYR-41
CAS#: 418805-02-4
Chemical Formula: C17H13N3O7
Exact Mass: 371.07535
Molecular Weight: 371.3
Elemental Analysis: C, 54.99; H, 3.53; N, 11.32; O, 30.16

Price and Availability

Size Price Availability Quantity
10.0mg USD 190.0 Ready to ship
25.0mg USD 250.0 Ready to ship
50.0mg USD 450.0 Ready to ship
100.0mg USD 850.0 Ready to ship
200.0mg USD 1250.0 Ready to ship
500.0mg USD 2150.0 2 Weeks
1.0g USD 2950.0 2 Weeks
2.0g USD 3950.0 2 Weeks
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Synonym: PYR41; PYR 41; PYR-41.

IUPAC/Chemical Name: ethyl 4-(4-((5-nitrofuran-2-yl)methylene)-3,5-dioxopyrazolidin-1-yl)benzoate

InChi Key: ARGIPZKQJGFSGQ-LCYFTJDESA-N

InChi Code: InChI=1S/C17H13N3O7/c1-2-26-17(23)10-3-5-11(6-4-10)19-16(22)13(15(21)18-19)9-12-7-8-14(27-12)20(24)25/h3-9H,2H2,1H3,(H,18,21)/b13-9-

SMILES Code: O=C(OCC)C1=CC=C(N2NC(/C(C2=O)=C/C3=CC=C([N+]([O-])=O)O3)=O)C=C1

Appearance: Brown solid powder

Purity: >98% (or refer to the Certificate of Analysis). Note: PYR-41 in solution may exist as a mixture of E- and Z- isomers. HPLC may show two peaks depending on conditions.

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Biological target: PYR-41 is a selective and cell permeable inhibitor of ubiquitin-activating enzyme E1 with an IC50 of < 10 μM, with little activity at E2 and E3
In vitro activity: In sepsis, release of proinflammatory cytokines from macrophages is the main cause of the “cytokine storm” (8). The effectiveness of PYR-41 in attenuating NF-κB activation in macrophages was first determined. The expression levels of IκB, an NF-κB inhibitor, in RAW 264.7 cells were decreased by 54% at 30 min after lipopolysaccharide (LPS) stimulation (Fig. 1A). With PYR-41 treatment at 10 and 20 μM, the expression levels of IκB were restored to 89% and 95% of those in the non LPS-stimulated RAW 264.7 cells, respectively (Fig. 1A). The TNF-α levels in cultured media grown with RAW 264.7 cells were then measured. After 4 h-LPS stimulation, the TNF-α levels increased from 0.03 to 1.34 ng/ml, while treatment with PYR-41 at doses of 5, 10, and 20 μM decreased TNF-α levels by 38%, 81%, and 94%, respectively (Fig. 1B). The viability of RAW 264.7 cells were also examined by MTS assay and observed no adverse effects of PYR-41 on cell viability (Fig. 1C). Shock. 2018 Apr; 49(4): 442–450. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5745315/
In vivo activity: PYR-41 was administered to mice that underwent sepsis-induction by CLP (cecal ligation and puncture). At 20 h after CLP, serum levels of proinflammatory cytokines TNF-α, IL-1β, and IL-6 were markedly increased compared to the sham (Fig. 2, A–C). In contrast, treatment with PYR-41 significantly reduced their levels by 79%, 77%, and 89%, respectively, compared to the vehicle (Fig. 2, A–C). Serum levels of organ injury markers AST, ALT, and LDH were also elevated after CLP, while their levels were reduced by 27%, 43%, and 52%, respectively, with PYR-41 treatment (Fig. 2, D–F). Additionalluy, after treatment with PYR-41, the morphologic appearance of lung tissues was improved (Fig. 3A). The severity of the lung damage was futher graded and showed a 74% reduction in histology injury score in the treatment group compared to the vehicle (Fig. 3B). Excessive immune cell infiltration, especially by neutrophils, is one important factor causing lung injury in sepsis (18). Lung myeloperoxidase (MPO) activity, a marker of neutrophil infiltration (19), was markedly increased after CLP by 19-fold compared to the sham, while it was significantly reduced by 64% with PYR-41 treatment compared to the vehicle (Fig. 3C). Shock. 2018 Apr; 49(4): 442–450. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5745315/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 20.0 53.9

Preparing Stock Solutions

The following data is based on the product molecular weight 371.3 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Matsuo S, Sharma A, Wang P, Yang WL. PYR-41, A Ubiquitin-Activating Enzyme E1 Inhibitor, Attenuates Lung Injury in Sepsis. Shock. 2018 Apr;49(4):442-450. doi: 10.1097/SHK.0000000000000931. PMID: 28661933; PMCID: PMC5745315. 2. You X, Xu DD, Zhang D, Chen J, Gao FG. PYR-41 and Thalidomide Impair Dendritic Cell Cross-Presentation by Inhibiting Myddosome Formation and Attenuating the Endosomal Recruitments of p97 and Sec61 via NF-κB Inactivation. J Immunol Res. 2018 Jul 5;2018:5070573. doi: 10.1155/2018/5070573. PMID: 30069488; PMCID: PMC6057288. 3. Shu Q, Lai S, Wang XM, Zhang YL, Yang XL, Bi HL, Li HH. Administration of ubiquitin-activating enzyme UBA1 inhibitor PYR-41 attenuates angiotensin II-induced cardiac remodeling in mice. Biochem Biophys Res Commun. 2018 Oct 20;505(1):317-324. doi: 10.1016/j.bbrc.2018.09.100. Epub 2018 Sep 22. PMID: 30249396.
In vitro protocol: 1. Matsuo S, Sharma A, Wang P, Yang WL. PYR-41, A Ubiquitin-Activating Enzyme E1 Inhibitor, Attenuates Lung Injury in Sepsis. Shock. 2018 Apr;49(4):442-450. doi: 10.1097/SHK.0000000000000931. PMID: 28661933; PMCID: PMC5745315. 2. You X, Xu DD, Zhang D, Chen J, Gao FG. PYR-41 and Thalidomide Impair Dendritic Cell Cross-Presentation by Inhibiting Myddosome Formation and Attenuating the Endosomal Recruitments of p97 and Sec61 via NF-κB Inactivation. J Immunol Res. 2018 Jul 5;2018:5070573. doi: 10.1155/2018/5070573. PMID: 30069488; PMCID: PMC6057288.
In vivo protocol: 1. Shu Q, Lai S, Wang XM, Zhang YL, Yang XL, Bi HL, Li HH. Administration of ubiquitin-activating enzyme UBA1 inhibitor PYR-41 attenuates angiotensin II-induced cardiac remodeling in mice. Biochem Biophys Res Commun. 2018 Oct 20;505(1):317-324. doi: 10.1016/j.bbrc.2018.09.100. Epub 2018 Sep 22. PMID: 30249396. 2. Matsuo S, Sharma A, Wang P, Yang WL. PYR-41, A Ubiquitin-Activating Enzyme E1 Inhibitor, Attenuates Lung Injury in Sepsis. Shock. 2018 Apr;49(4):442-450. doi: 10.1097/SHK.0000000000000931. PMID: 28661933; PMCID: PMC5745315.

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1: Su H, Chen M, Sands JM, Chen G. Activation of the cAMP/PKA pathway induces UT-A1 urea transporter monoubiquitination and targets it for lysosomal degradation. Am J Physiol Renal Physiol. 2013 Dec 15;305(12):F1775-82. doi: 10.1152/ajprenal.00393.2013. Epub 2013 Oct 16. PubMed PMID: 24133116; PubMed Central PMCID: PMC3882448.

2: Londino JD, Lazrak A, Jurkuvenaite A, Collawn JF, Noah JW, Matalon S. Influenza matrix protein 2 alters CFTR expression and function through its ion channel activity. Am J Physiol Lung Cell Mol Physiol. 2013 May 1;304(9):L582-92. doi: 10.1152/ajplung.00314.2012. Epub 2013 Mar 1. PubMed PMID: 23457187; PubMed Central PMCID: PMC3652020.

3: Xu H, Luo P, Zhao Y, Zhao M, Yang Y, Chen T, Huo K, Han H, Fei Z. Iduna protects HT22 cells from hydrogen peroxide-induced oxidative stress through interfering poly(ADP-ribose) polymerase-1-induced cell death (parthanatos). Cell Signal. 2013 Apr;25(4):1018-26. doi: 10.1016/j.cellsig.2013.01.006. Epub 2013 Jan 16. PubMed PMID: 23333241.

4: Moudry P, Lukas C, Macurek L, Hanzlikova H, Hodny Z, Lukas J, Bartek J. Ubiquitin-activating enzyme UBA1 is required for cellular response to DNA damage. Cell Cycle. 2012 Apr 15;11(8):1573-82. doi: 10.4161/cc.19978. Epub 2012 Apr 15. PubMed PMID: 22456334.

5: Guan H, Ricciardi RP. Transformation by E1A oncoprotein involves ubiquitin-mediated proteolysis of the neuronal and tumor repressor REST in the nucleus. J Virol. 2012 May;86(10):5594-602. doi: 10.1128/JVI.06811-11. Epub 2012 Mar 14. PubMed PMID: 22419809; PubMed Central PMCID: PMC3347283.

6: Haines DS, Lee JE, Beauparlant SL, Kyle DB, den Besten W, Sweredoski MJ, Graham RL, Hess S, Deshaies RJ. Protein interaction profiling of the p97 adaptor UBXD1 points to a role for the complex in modulating ERGIC-53 trafficking. Mol Cell Proteomics. 2012 Jun;11(6):M111.016444. doi: 10.1074/mcp.M111.016444. Epub 2012 Feb 14. PubMed PMID: 22337587; PubMed Central PMCID: PMC3433925.

7: Ungermannova D, Parker SJ, Nasveschuk CG, Chapnick DA, Phillips AJ, Kuchta RD, Liu X. Identification and mechanistic studies of a novel ubiquitin E1 inhibitor. J Biomol Screen. 2012 Apr;17(4):421-34. doi: 10.1177/1087057111433843. Epub 2012 Jan 24. PubMed PMID: 22274912; PubMed Central PMCID: PMC3339042.

8: Fei J, Kaczmarek N, Luch A, Glas A, Carell T, Naegeli H. Regulation of nucleotide excision repair by UV-DDB: prioritization of damage recognition to internucleosomal DNA. PLoS Biol. 2011 Oct;9(10):e1001183. doi: 10.1371/journal.pbio.1001183. Epub 2011 Oct 25. PubMed PMID: 22039351; PubMed Central PMCID: PMC3201922.

9: Yi YJ, Zimmerman SW, Manandhar G, Odhiambo JF, Kennedy C, Jonáková V, Maňásková-Postlerová P, Sutovsky M, Park CS, Sutovsky P. Ubiquitin-activating enzyme (UBA1) is required for sperm capacitation, acrosomal exocytosis and sperm-egg coat penetration during porcine fertilization. Int J Androl. 2012 Apr;35(2):196-210. doi: 10.1111/j.1365-2605.2011.01217.x. Epub 2011 Sep 27. PubMed PMID: 21950462.

10: Kapuria V, Peterson LF, Showalter HD, Kirchhoff PD, Talpaz M, Donato NJ. Protein cross-linking as a novel mechanism of action of a ubiquitin-activating enzyme inhibitor with anti-tumor activity. Biochem Pharmacol. 2011 Aug 15;82(4):341-9. doi: 10.1016/j.bcp.2011.05.012. Epub 2011 May 19. PubMed PMID: 21621524.

11: Russell MA, Morgan NG. Conditional expression of the FTO gene product in rat INS-1 cells reveals its rapid turnover and a role in the profile of glucose-induced insulin secretion. Clin Sci (Lond). 2011 May;120(9):403-13. doi: 10.1042/CS20100416. PubMed PMID: 21070190.

12: Tominaga K, Tominaga E, Ausserlechner MJ, Pereira-Smith OM. The cell senescence inducing gene product MORF4 is regulated by degradation via the ubiquitin/proteasome pathway. Exp Cell Res. 2010 Jan 1;316(1):92-102. doi: 10.1016/j.yexcr.2009.09.015. Epub 2009 Sep 19. PubMed PMID: 19769966; PubMed Central PMCID: PMC2787921.

13: Yang Y, Kitagaki J, Dai RM, Tsai YC, Lorick KL, Ludwig RL, Pierre SA, Jensen JP, Davydov IV, Oberoi P, Li CC, Kenten JH, Beutler JA, Vousden KH, Weissman AM. Inhibitors of ubiquitin-activating enzyme (E1), a new class of potential cancer therapeutics. Cancer Res. 2007 Oct 1;67(19):9472-81. PubMed PMID: 17909057.

14: Samulack DD, Williams S, Lacaille JC. Hyperpolarizing synaptic potentials evoked in CA1 pyramidal cells by glutamate stimulation of interneurons from the oriens/alveus border of rat hippocampal slices. I. Electrophysiological response properties. Hippocampus. 1993 Jul;3(3):331-44. PubMed PMID: 8102582.

PYR-41

10.0mg / USD 190.0


Additional Information

  Note: PYR-41, in solution, may exist as a mixture of E- and Z- isomers in a ratio of 1:1. HPLC may show two peaks.