PYR-41 | CAS#418805-02-4 | ubiquitin-activating enzyme inhibitor

MedKoo Cat#: 406481 | Name: PYR-41

Description:

WARNING: This product is for research use only, not for human or veterinary use.

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

PYR-41

CAS#418805-02-4

Theoretical Analysis

MedKoo Cat#: 406481

Name: PYR-41

CAS#: 418805-02-4

Chemical Formula: C17H13N3O7

Exact Mass: 371.0754

Molecular Weight: 371.30

Elemental Analysis: C, 54.99; H, 3.53; N, 11.32; O, 30.16

Price and Availability

Size	Price	Availability
10mg	USD 150.00	Ready to ship
25mg	USD 250.00	Ready to ship
50mg	USD 450.00	Ready to ship
100mg	USD 750.00	Ready to ship
200mg	USD 1,350.00	Ready to ship

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Related CAS #

No Data

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

More Info

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.

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, Lot#TZC50918

QC Data

View QC data: current batch, Lot#TZC50918

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

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/

	Solvent	mg/mL	mM
Solubility
	DMSO	20.0	53.90

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 371.30 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.

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:

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.

1: Kociper B, Škorja Milić N, Ogrizek I, Miš K, Pirkmajer S. Inhibition of the ubiquitin-proteasome system reduces the abundance of pyruvate dehydrogenase kinase 1 in cultured myotubes. J Muscle Res Cell Motil. 2024 Sep;45(3):155-169. doi: 10.1007/s10974-024-09679-3. Epub 2024 Jul 31. PMID: 39080182; PMCID: PMC11316709. 2: Yuan X, Zhang X, Wang H, Mao X, Sun Y, Tan L, Song C, Qiu X, Ding C, Liao Y. The Ubiquitin-Proteasome System Facilitates Membrane Fusion and Uncoating during Coronavirus Entry. Viruses. 2023 Sep 26;15(10):2001. doi: 10.3390/v15102001. PMID: 37896778; PMCID: PMC10610886. 3: Yang L, Zhang Q, Yang Y, Wang Q. PYR-41, an inhibitor of ubiquitin-activating enzyme E1, attenuates 2,4-dinitrochlorobenzene-induced atopic dermatitis-like skin lesions in mice. FASEB J. 2023 Oct;37(10):e23210. doi: 10.1096/fj.202200951RRR. PMID: 37738047. 4: Sawada H, Inoue S, Saito T, Otsuka K, Shirae-Kurabayashi M. Involvement in Fertilization and Expression of Gamete Ubiquitin-Activating Enzymes UBA1 and UBA6 in the Ascidian Halocynthia roretzi. Int J Mol Sci. 2023 Jun 26;24(13):10662. doi: 10.3390/ijms241310662. PMID: 37445840; PMCID: PMC10341865. 5: Goeckeler-Fried JL, Aldrin Denny R, Joshi D, Hill C, Larsen MB, Chiang AN, Frizzell RA, Wipf P, Sorscher EJ, Brodsky JL. Improved correction of F508del- CFTR biogenesis with a folding facilitator and an inhibitor of protein ubiquitination. Bioorg Med Chem Lett. 2021 Sep 15;48:128243. doi: 10.1016/j.bmcl.2021.128243. Epub 2021 Jul 8. PMID: 34246753; PMCID: PMC8869796. 6: Parkhitko AA, Singh A, Hsieh S, Hu Y, Binari R, Lord CJ, Hannenhalli S, Ryan CJ, Perrimon N. Cross-species identification of PIP5K1-, splicing- and ubiquitin-related pathways as potential targets for RB1-deficient cells. PLoS Genet. 2021 Feb 16;17(2):e1009354. doi: 10.1371/journal.pgen.1009354. PMID: 33591981; PMCID: PMC7909629. 7: Ikeda M, Ito A, Sekine Y, Fujimuro M. UBE1a Suppresses Herpes Simplex Virus-1 Replication. Viruses. 2020 Dec 4;12(12):1391. doi: 10.3390/v12121391. PMID: 33291814; PMCID: PMC7762088. 8: Wang L, Li M, Sha B, Hu X, Sun Y, Zhu M, Xu Y, Li P, Wang Y, Guo Y, Li J, Shi J, Li P, Hu T, Chen P. Inhibition of deubiquitination by PR-619 induces apoptosis and autophagy via ubi-protein aggregation-activated ER stress in oesophageal squamous cell carcinoma. Cell Prolif. 2021 Jan;54(1):e12919. doi: 10.1111/cpr.12919. Epub 2020 Oct 31. PMID: 33129231; PMCID: PMC7791184. 9: Millen S, Meretuk L, Göttlicher T, Schmitt S, Fleckenstein B, Thoma-Kress AK. A novel positive feedback-loop between the HTLV-1 oncoprotein Tax and NF-κB activity in T-cells. Retrovirology. 2020 Sep 10;17(1):30. doi: 10.1186/s12977-020-00538-w. PMID: 32912211; PMCID: PMC7488018. 10: Nánási P Jr, Imre L, Firouzi Niaki E, Bosire R, Mocsár G, Türk-Mázló A, Ausio J, Szabó G. Doxorubicin induces large-scale and differential H2A and H2B redistribution in live cells. PLoS One. 2020 Apr 16;15(4):e0231223. doi: 10.1371/journal.pone.0231223. PMID: 32298286; PMCID: PMC7162453. 11: Park Y, Ku L, Lim JW, Kim H. Docosahexaenoic acid inhibits zymogen activation by suppressing vacuolar ATPase activation in cerulein-stimulated pancreatic acinar cells. Genes Nutr. 2020 Mar 23;15(1):6. doi: 10.1186/s12263-020-00664-2. PMID: 32293245; PMCID: PMC7092610. 12: Liao J, Yang X, Lin Q, Liu S, Xie Y, Xia Y, Li HH. Inhibition of the Ubiquitin-Activating Enzyme UBA1 Suppresses Diet-Induced Atherosclerosis in Apolipoprotein E-Knockout Mice. J Immunol Res. 2020 Mar 20;2020:7812709. doi: 10.1155/2020/7812709. PMID: 32258175; PMCID: PMC7109586. 13: Takabatake M, Goshima Y, Sasaki Y. Semaphorin-3A Promotes Degradation of Fragile X Mental Retardation Protein in Growth Cones via the Ubiquitin- Proteasome Pathway. Front Neural Circuits. 2020 Feb 28;14:5. doi: 10.3389/fncir.2020.00005. PMID: 32184710; PMCID: PMC7059091. 14: Ning F, Xin H, Liu J, Lv C, Xu X, Wang M, Wang Y, Zhang W, Zhang X. Structure and function of USP5: Insight into physiological and pathophysiological roles. Pharmacol Res. 2020 Jul;157:104557. doi: 10.1016/j.phrs.2019.104557. Epub 2019 Nov 19. PMID: 31756387. 15: Imai J, Koganezawa Y, Tuzuki H, Ishikawa I, Sakai T. An optical and non- invasive method to detect the accumulation of ubiquitin chains. Cell Biol Int. 2019 Dec;43(12):1393-1406. doi: 10.1002/cbin.11186. Epub 2019 Jun 18. PMID: 31136031. 16: Itoh A, Nonaka Y, Ogawa T, Nakamura T, Nishi N. Galectin-9 induces atypical ubiquitination leading to cell death in PC-3 prostate cancer cells. Glycobiology. 2019 Jan 1;29(1):22-35. doi: 10.1093/glycob/cwy099. PMID: 30383222. 17: Monda JK, Cheeseman IM. Dynamic regulation of dynein localization revealed by small molecule inhibitors of ubiquitination enzymes. Open Biol. 2018 Sep 26;8(9):180095. doi: 10.1098/rsob.180095. PMID: 30257893; PMCID: PMC6170511. 18: 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. 19: 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. 20: Matsuo S, Chaung A, Liou D, Wang P, Yang WL. Inhibition of ubiquitin- activating enzyme protects against organ injury after intestinal ischemia- reperfusion. Am J Physiol Gastrointest Liver Physiol. 2018 Aug 1;315(2):G283-G292. doi: 10.1152/ajpgi.00024.2018. Epub 2018 May 17. PMID: 29771572; PMCID: PMC6139649.