WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 530345
CAS#: 1597403-47-8 (trans-isomer)
Description: trans-ISRIB is an Integrated Stress Response Inhibitor. trans-ISRIB inhibits the eIF2α phosphorylation-mediated unfolded protein response following induction of ER stress (IC50 = 5 nM in a cell-reporter assay). ISRIB reverses the effects of eIF2α phosphorylation on translation and stress granule assembly. ISRIB reverses the effects of eIF2α phosphorylation on translation and stress granule assembly
MedKoo Cat#: 530345
Name: trans-ISRIB
CAS#: 1597403-47-8 (trans-isomer)
Chemical Formula: C22H24Cl2N2O4
Exact Mass: 450.1113
Molecular Weight: 451.344
Elemental Analysis: C, 58.55; H, 5.36; Cl, 15.71; N, 6.21; O, 14.18
Related CAS #: 1597403-47-8 (trans-isomer) 548470-11-7
Synonym: trans-ISRIB
IUPAC/Chemical Name: N,N'-((1r,4r)-cyclohexane-1,4-diyl)bis(2-(4-chlorophenoxy)acetamide)
InChi Key: HJGMCDHQPXTGAV-IYARVYRRSA-N
InChi Code: InChI=1S/C22H24Cl2N2O4/c23-15-1-9-19(10-2-15)29-13-21(27)25-17-5-7-18(8-6-17)26-22(28)14-30-20-11-3-16(24)4-12-20/h1-4,9-12,17-18H,5-8,13-14H2,(H,25,27)(H,26,28)/t17-,18-
SMILES Code: O=C(N[C@H]1CC[C@H](NC(COC2=CC=C(Cl)C=C2)=O)CC1)COC3=CC=C(Cl)C=C3
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: | ISRIB is an integrated stress response (ISR) inhibitor that potently reverses the effects of eukaryotic initiation factor 2α (eIF2α) phosphorylation with IC50 of 5 nM. |
| In vitro activity: | Given that PERK phosphorylation was not diminished in ISRIB-treated, ER-stressed cells, next eIF2α phosphorylation was directly assessed. The levels of phosphorylated eIF2α were measured using an antiphospho-eIF2α antibody-based assay to quantify phosphorylation at serine 51 (see ‘Materials and methods’). Upon induction of ER stress by tunicamycin or thapsigargin, phosphorylation of eIF2α increased over time, reaching a fourfold and sevenfold increase after 120 min respectively. Unexpectedly, ISRIB did not block eIF2α phosphorylation under either of these ER stress-inducing conditions. On the contrary, 120 min after tunicamycin addition, ISRIB further increased the level of eIF2α phosphorylation, approaching that obtained with thapsigargin. ISRIB alone had no effect on eIF2α phosphorylation. These results indicate that ISRIB blocks effects downstream of PERK and eIF2α phosphorylation. Reference: Elife. 2013 May 28;2:e00498. https://pubmed.ncbi.nlm.nih.gov/23741617/ |
| In vivo activity: | Treatment with ISRIB decreased the number of GFP+Siglec Flow monocyte-derived alveolar macrophages at day 14 after bleomycin in both young adult and old mice. To determine whether this reduction of monocyte-derived alveolar macrophages after treatment with ISRIB was attributable to reduced proliferation, mice were treated with EdU for 3 d before harvest. It was found that after administration of bleomycin, tissue-resident and monocyte-derived alveolar macrophages in old mice showed increased incorporation of EdU compared with young adult mice. The enhanced proliferation of tissue-resident and monocyte-derived alveolar macrophages in old mice 21 d after bleomycin was not observed in ISRIB-treated mice. Collectively, these results suggest that ISRIB either reduces the recruitment or inhibits factors required for the maintenance of monocyte-derived alveolar macrophages during bleomycin-induced fibrosis irrespective of age. Reference: Proc Natl Acad Sci U S A. 2021 May 18;118(20):e2101100118. https://pubmed.ncbi.nlm.nih.gov/33972447/ |
| Solvent | Max Conc. mg/mL | Max Conc. mM | |
|---|---|---|---|
| Solubility | |||
| DMSO | 5.5 | 12.19 |
The following data is based on the product molecular weight 451.344 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. Zyryanova AF, Kashiwagi K, Rato C, Harding HP, Crespillo-Casado A, Perera LA, Sakamoto A, Nishimoto M, Yonemochi M, Shirouzu M, Ito T, Ron D. ISRIB Blunts the Integrated Stress Response by Allosterically Antagonising the Inhibitory Effect of Phosphorylated eIF2 on eIF2B. Mol Cell. 2021 Jan 7;81(1):88-103.e6. doi: 10.1016/j.molcel.2020.10.031. Epub 2020 Nov 20. PMID: 33220178; PMCID: PMC7837216. 2. Sidrauski C, Acosta-Alvear D, Khoutorsky A, Vedantham P, Hearn BR, Li H, Gamache K, Gallagher CM, Ang KK, Wilson C, Okreglak V, Ashkenazi A, Hann B, Nader K, Arkin MR, Renslo AR, Sonenberg N, Walter P. Pharmacological brake-release of mRNA translation enhances cognitive memory. Elife. 2013 May 28;2:e00498. doi: 10.7554/eLife.00498. PMID: 23741617; PMCID: PMC3667625. 3. . Watanabe S, Markov NS, Lu Z, Piseaux Aillon R, Soberanes S, Runyan CE, Ren Z, Grant RA, Maciel M, Abdala-Valencia H, Politanska Y, Nam K, Sichizya L, Kihshen HG, Joshi N, McQuattie-Pimentel AC, Gruner KA, Jain M, Sznajder JI, Morimoto RI, Reyfman PA, Gottardi CJ, Budinger GRS, Misharin AV. Resetting proteostasis with ISRIB promotes epithelial differentiation to attenuate pulmonary fibrosis. Proc Natl Acad Sci U S A. 2021 May 18;118(20):e2101100118. doi: 10.1073/pnas.2101100118. PMID: 33972447; PMCID: PMC8157939. 4. Sidrauski C, McGeachy AM, Ingolia NT, Walter P. The small molecule ISRIB reverses the effects of eIF2α phosphorylation on translation and stress granule assembly. Elife. 2015 Feb 26;4:e05033. doi: 10.7554/eLife.05033. PMID: 25719440; PMCID: PMC4341466. |
| In vitro protocol: | 1. Zyryanova AF, Kashiwagi K, Rato C, Harding HP, Crespillo-Casado A, Perera LA, Sakamoto A, Nishimoto M, Yonemochi M, Shirouzu M, Ito T, Ron D. ISRIB Blunts the Integrated Stress Response by Allosterically Antagonising the Inhibitory Effect of Phosphorylated eIF2 on eIF2B. Mol Cell. 2021 Jan 7;81(1):88-103.e6. doi: 10.1016/j.molcel.2020.10.031. Epub 2020 Nov 20. PMID: 33220178; PMCID: PMC7837216. 2. Sidrauski C, Acosta-Alvear D, Khoutorsky A, Vedantham P, Hearn BR, Li H, Gamache K, Gallagher CM, Ang KK, Wilson C, Okreglak V, Ashkenazi A, Hann B, Nader K, Arkin MR, Renslo AR, Sonenberg N, Walter P. Pharmacological brake-release of mRNA translation enhances cognitive memory. Elife. 2013 May 28;2:e00498. doi: 10.7554/eLife.00498. PMID: 23741617; PMCID: PMC3667625. |
| In vivo protocol: | 1. Watanabe S, Markov NS, Lu Z, Piseaux Aillon R, Soberanes S, Runyan CE, Ren Z, Grant RA, Maciel M, Abdala-Valencia H, Politanska Y, Nam K, Sichizya L, Kihshen HG, Joshi N, McQuattie-Pimentel AC, Gruner KA, Jain M, Sznajder JI, Morimoto RI, Reyfman PA, Gottardi CJ, Budinger GRS, Misharin AV. Resetting proteostasis with ISRIB promotes epithelial differentiation to attenuate pulmonary fibrosis. Proc Natl Acad Sci U S A. 2021 May 18;118(20):e2101100118. doi: 10.1073/pnas.2101100118. PMID: 33972447; PMCID: PMC8157939. 2. Sidrauski C, McGeachy AM, Ingolia NT, Walter P. The small molecule ISRIB reverses the effects of eIF2α phosphorylation on translation and stress granule assembly. Elife. 2015 Feb 26;4:e05033. doi: 10.7554/eLife.05033. PMID: 25719440; PMCID: PMC4341466. |
1: Zyryanova AF, Kashiwagi K, Rato C, Harding HP, Crespillo-Casado A, Perera LA, Sakamoto A, Nishimoto M, Yonemochi M, Shirouzu M, Ito T, Ron D. ISRIB Blunts the Integrated Stress Response by Allosterically Antagonising the Inhibitory Effect of Phosphorylated eIF2 on eIF2B. Mol Cell. 2021 Jan 7;81(1):88-103.e6. doi: 10.1016/j.molcel.2020.10.031. Epub 2020 Nov 20. PMID: 33220178; PMCID: PMC7837216.
2: Bugallo R, Marlin E, Baltanás A, Toledo E, Ferrero R, Vinueza-Gavilanes R, Larrea L, Arrasate M, Aragón T. Fine tuning of the unfolded protein response by ISRIB improves neuronal survival in a model of amyotrophic lateral sclerosis. Cell Death Dis. 2020 May 26;11(5):397. doi: 10.1038/s41419-020-2601-2. PMID: 32457286; PMCID: PMC7250913.
3: Young-Baird SK, Lourenço MB, Elder MK, Klann E, Liebau S, Dever TE. Suppression of MEHMO Syndrome Mutation in eIF2 by Small Molecule ISRIB. Mol Cell. 2020 Feb 20;77(4):875-886.e7. doi: 10.1016/j.molcel.2019.11.008. Epub 2019 Dec 10. PMID: 31836389; PMCID: PMC7035991.
4: Anand AA, Walter P. Structural insights into ISRIB, a memory-enhancing inhibitor of the integrated stress response. FEBS J. 2020 Jan;287(2):239-245. doi: 10.1111/febs.15073. Epub 2019 Nov 7. PMID: 31550413.
5: Rabouw HH, Langereis MA, Anand AA, Visser LJ, de Groot RJ, Walter P, van Kuppeveld FJM. Small molecule ISRIB suppresses the integrated stress response within a defined window of activation. Proc Natl Acad Sci U S A. 2019 Feb 5;116(6):2097-2102. doi: 10.1073/pnas.1815767116. Epub 2019 Jan 23. PMID: 30674674; PMCID: PMC6369741.
6: Zyryanova AF, Weis F, Faille A, Alard AA, Crespillo-Casado A, Sekine Y, Harding HP, Allen F, Parts L, Fromont C, Fischer PM, Warren AJ, Ron D. Binding of ISRIB reveals a regulatory site in the nucleotide exchange factor eIF2B. Science. 2018 Mar 30;359(6383):1533-1536. doi: 10.1126/science.aar5129. PMID: 29599245; PMCID: PMC5889100.
7: Wong YL, LeBon L, Edalji R, Lim HB, Sun C, Sidrauski C. The small molecule ISRIB rescues the stability and activity of Vanishing White Matter Disease eIF2B mutant complexes. Elife. 2018 Feb 28;7:e32733. doi: 10.7554/eLife.32733. PMID: 29489452; PMCID: PMC5829914.
8: Hosoi T, Kakimoto M, Tanaka K, Nomura J, Ozawa K. Unique pharmacological property of ISRIB in inhibition of Aβ-induced neuronal cell death. J Pharmacol Sci. 2016 Aug;131(4):292-5. doi: 10.1016/j.jphs.2016.08.003. Epub 2016 Aug 12. PMID: 27569458.
9: Halliday M, Radford H, Sekine Y, Moreno J, Verity N, le Quesne J, Ortori CA, Barrett DA, Fromont C, Fischer PM, Harding HP, Ron D, Mallucci GR. Partial restoration of protein synthesis rates by the small molecule ISRIB prevents neurodegeneration without pancreatic toxicity. Cell Death Dis. 2015 Mar 5;6(3):e1672. doi: 10.1038/cddis.2015.49. PMID: 25741597; PMCID: PMC4385927.
10: Sidrauski C, McGeachy AM, Ingolia NT, Walter P. The small molecule ISRIB reverses the effects of eIF2α phosphorylation on translation and stress granule assembly. Elife. 2015 Feb 26;4:e05033. doi: 10.7554/eLife.05033. PMID: 25719440; PMCID: PMC4341466.
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