WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 530969
Description: 4μ8C, also known as IRE1 Inhibitor III, is a IRE1 Inhibitor. 4µ8C inhibits IRE1α splicing of Xbp1 mRNA (IC50 = 6.8 µM) and reduces subsequent gene expression of Erdj4 (IC50 = 3.4 µM) in stress-cultured MEF cells but does not block IRE1α autophosphorylation.
MedKoo Cat#: 530969
Chemical Formula: C11H8O4
Exact Mass: 204.0423
Molecular Weight: 204.181
Elemental Analysis: C, 64.71; H, 3.95; O, 31.34
Synonym: 4μ8C; 4Mu8C; 4u8C;4U8C;
IUPAC/Chemical Name: 7-hydroxy-4-methyl-2-oxo-2H-1-benzopyran-8-carboxaldehyde
InChi Key: RTHHSXOVIJWFQP-UHFFFAOYSA-N
InChi Code: InChI=1S/C11H8O4/c1-6-4-10(14)15-11-7(6)2-3-9(13)8(11)5-12/h2-5,13H,1H3
SMILES Code: O=CC1=C(O2)C(C(C)=CC2=O)=CC=C1O
Appearance: Solid powder
Purity: >98% (or refer to the Certificate of Analysis)
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
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:||4μ8C (IRE1 Inhibitor III) is a small-molecule inhibitor of IRE1α.|
|In vitro activity:||To further confirm the role of IRE1α in IL-4 production, the effects of an IRE1α inhibitor, 4μ8C, was investigated on IL-4 expression in an in vitro culture system. On average, an ∼60% reduction in Xbp-1 splicing was confirmed by qRT-PCR (Fig. 4A) upon treatment of CD4+ T cells with the inhibitor. It was found that 4μ8C treatment dramatically inhibits IL-4 production by CD4+ T cells under Th0 conditions because both the IL-4 levels in the culture supernatant and the percentage of IL-4 positive cells were reduced by 4μ8C treatment (Fig. 4, B–D). In contrast, the expression of IFN-γ did not appear to be affected by IRE1α inhibitor 4μ8C (Fig. 4, B–D). These led us to conclude that the suppression of IRE1α functions in T cells blocks IL-4 production. In addition, both IL-5 and IL-13 production were significantly reduced upon treatment with 4μ8C (Fig. 4D). In contrast, cytokines IFN-γ and IL-17 appeared to be normal (Fig. 3D). Therefore, the pharmacological suppression of IRE1α inhibits the production of all Th2 cytokines analyzed in CD4 T cells, whereas diminished expression of IRE1α leads to reduced IL-4 but not IL-5 and IL-13. Reference: J Biol Chem. 2013 Nov 15;288(46):33272-82. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24100031/|
|In vivo activity:||4μ8c treatment led to a significant reduction (45.2%; P < 0.001) in atherosclerotic lesion area in en face aorta preparations (Fig. 4E) and a significant reduction in the spliced Xbp1 mRNA (Fig. S7A) (P < 0.05) but no change in IRE1 phosphorylation in the spleens (Fig. S7B). Furthermore, 4μ8c treatment led to a reduced foam cell area (Fig. 4F) without overt differences in body weight, blood glucose levels (Table S4), liver morphology, and plasma ALT activity between the inhibitor-treated and control mice (Fig. S7 C and D). These in vivo findings show that pharmacological inhibition of IRE1 can effectively mitigate plaque development in mice. Reference: Proc Natl Acad Sci U S A. 2017 Feb 21;114(8):E1395-E1404. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/28137856/|
|Solvent||Max Conc. mg/mL||Max Conc. mM|
The following data is based on the product molecular weight 204.181 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|
|In vitro protocol:||1. Kemp KL, Lin Z, Zhao F, Gao B, Song J, Zhang K, Fang D. The serine-threonine kinase inositol-requiring enzyme 1α (IRE1α) promotes IL-4 production in T helper cells. J Biol Chem. 2013 Nov 15;288(46):33272-82. doi: 10.1074/jbc.M113.493171. Epub 2013 Oct 7. PMID: 24100031; PMCID: PMC3829173. 2. Zhang L, Nosak C, Sollazzo P, Odisho T, Volchuk A. IRE1 inhibition perturbs the unfolded protein response in a pancreatic β-cell line expressing mutant proinsulin, but does not sensitize the cells to apoptosis. BMC Cell Biol. 2014 Jul 10;15:29. doi: 10.1186/1471-2121-15-29. PMID: 25011481; PMCID: PMC4118655.|
|In vivo protocol:||1. Tufanli O, Telkoparan Akillilar P, Acosta-Alvear D, Kocaturk B, Onat UI, Hamid SM, Çimen I, Walter P, Weber C, Erbay E. Targeting IRE1 with small molecules counteracts progression of atherosclerosis. Proc Natl Acad Sci U S A. 2017 Feb 21;114(8):E1395-E1404. doi: 10.1073/pnas.1621188114. Epub 2017 Jan 30. PMID: 28137856; PMCID: PMC5338400.|
1: Guo Q, Jin S, Hu H, Zhou Y, Yan Y, Zong H, Wang Y, He H, Oh Y, Liu C, Gu N. Hypoxia in 3T3-L1 adipocytes suppresses adiponectin expression via the PERK and IRE1 unfolded protein response. Biochem Biophys Res Commun. 2017 Nov 4;493(1):346-351. doi: 10.1016/j.bbrc.2017.09.020. Epub 2017 Sep 6. PubMed PMID: 28888981.
2: Li XX, Zhang HS, Xu YM, Zhang RJ, Chen Y, Fan L, Qin YQ, Liu Y, Li M, Fang J. Knockdown of IRE1α inhibits colonic tumorigenesis through decreasing β-catenin and IRE1α targeting suppresses colon cancer cells. Oncogene. 2017 Aug 21. doi: 10.1038/onc.2017.284. [Epub ahead of print] PubMed PMID: 28825721.
3: Nam ST, Park YH, Kim HW, Kim HS, Lee D, Lee MB, Kim YM, Choi WS. Suppression of IgE-mediated mast cell activation and mouse anaphylaxis via inhibition of Syk activation by 8-formyl-7-hydroxy-4-methylcoumarin, 4μ8C. Toxicol Appl Pharmacol. 2017 Oct 1;332:25-31. doi: 10.1016/j.taap.2017.07.015. Epub 2017 Jul 20. PubMed PMID: 28736076.
4: Takahashi N, Kimura AP, Naito S, Yoshida M, Kumano O, Suzuki T, Itaya S, Moriya M, Tsuji M, Ieko M. Sarcolipin expression is repressed by endoplasmic reticulum stress in C2C12 myotubes. J Physiol Biochem. 2017 Nov;73(4):531-538. doi: 10.1007/s13105-017-0578-9. Epub 2017 Jul 13. PubMed PMID: 28707279.
5: Sato H, Shiba Y, Tsuchiya Y, Saito M, Kohno K. 4μ8C Inhibits Insulin Secretion Independent of IRE1α RNase Activity. Cell Struct Funct. 2017 May 3;42(1):61-70. doi: 10.1247/csf.17002. Epub 2017 Mar 18. PubMed PMID: 28321016.
6: Chen C, Zhang X. IRE1α-XBP1 pathway promotes melanoma progression by regulating IL-6/STAT3 signaling. J Transl Med. 2017 Feb 21;15(1):42. doi: 10.1186/s12967-017-1147-2. PubMed PMID: 28222747; PubMed Central PMCID: PMC5320675.
7: Ma JH, Wang JJ, Li J, Pfeffer BA, Zhong Y, Zhang SX. The Role of IRE-XBP1 Pathway in Regulation of Retinal Pigment Epithelium Tight Junctions. Invest Ophthalmol Vis Sci. 2016 Oct 1;57(13):5244-5252. doi: 10.1167/iovs.16-19232. PubMed PMID: 27701635; PubMed Central PMCID: PMC5054729.
8: Heindryckx F, Binet F, Ponticos M, Rombouts K, Lau J, Kreuger J, Gerwins P. Endoplasmic reticulum stress enhances fibrosis through IRE1α-mediated degradation of miR-150 and XBP-1 splicing. EMBO Mol Med. 2016 Jul 1;8(7):729-44. doi: 10.15252/emmm.201505925. Print 2016 Jul. PubMed PMID: 27226027; PubMed Central PMCID: PMC4931288.
9: Lubamba BA, Jones LC, O'Neal WK, Boucher RC, Ribeiro CM. X-Box-Binding Protein 1 and Innate Immune Responses of Human Cystic Fibrosis Alveolar Macrophages. Am J Respir Crit Care Med. 2015 Dec 15;192(12):1449-61. doi: 10.1164/rccm.201504-0657OC. PubMed PMID: 26331676; PubMed Central PMCID: PMC4731720.
10: Storniolo A, Raciti M, Cucina A, Bizzarri M, Di Renzo L. Quercetin affects Hsp70/IRE1α mediated protection from death induced by endoplasmic reticulum stress. Oxid Med Cell Longev. 2015;2015:645157. doi: 10.1155/2015/645157. Epub 2015 Apr 2. PubMed PMID: 25922642; PubMed Central PMCID: PMC4398920.
11: Zhang L, Nosak C, Sollazzo P, Odisho T, Volchuk A. IRE1 inhibition perturbs the unfolded protein response in a pancreatic β-cell line expressing mutant proinsulin, but does not sensitize the cells to apoptosis. BMC Cell Biol. 2014 Jul 10;15:29. doi: 10.1186/1471-2121-15-29. PubMed PMID: 25011481; PubMed Central PMCID: PMC4118655.
12: Kemp KL, Lin Z, Zhao F, Gao B, Song J, Zhang K, Fang D. The serine-threonine kinase inositol-requiring enzyme 1α (IRE1α) promotes IL-4 production in T helper cells. J Biol Chem. 2013 Nov 15;288(46):33272-82. doi: 10.1074/jbc.M113.493171. Epub 2013 Oct 7. PubMed PMID: 24100031; PubMed Central PMCID: PMC3829173.
13: Cojocari D, Vellanki RN, Sit B, Uehling D, Koritzinsky M, Wouters BG. New small molecule inhibitors of UPR activation demonstrate that PERK, but not IRE1α signaling is essential for promoting adaptation and survival to hypoxia. Radiother Oncol. 2013 Sep;108(3):541-7. doi: 10.1016/j.radonc.2013.06.005. Epub 2013 Jul 3. PubMed PMID: 23830192.
14: Cross BC, Bond PJ, Sadowski PG, Jha BK, Zak J, Goodman JM, Silverman RH, Neubert TA, Baxendale IR, Ron D, Harding HP. The molecular basis for selective inhibition of unconventional mRNA splicing by an IRE1-binding small molecule. Proc Natl Acad Sci U S A. 2012 Apr 10;109(15):E869-78. doi: 10.1073/pnas.1115623109. Epub 2012 Feb 6. PubMed PMID: 22315414; PubMed Central PMCID: PMC3326519.