ArticleBritish journal of pharmacology2013
Selective, potent blockade of the IRE1 and ATF6 pathways by 4-phenylbutyric acid analogues.
Article in British journal of pharmacology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 32 citations in OpenAlex.
- A novel 14-deoxy-12-hydroxyandrographolide analogue promotes apoptosis in colorectal cancer through ROS-dependent endoplasmic reticulum stress activation.Discover oncology · 2026Article
- ER stress-induced ITPR1/ANO1 signaling drives trigeminal neuropathic pain through calcium-dependent neuronal hyperexcitability.The journal of headache and pain · 2025Article
- Preventing unfolded protein response-induced ion channel dysregulation to treat arrhythmias.Trends in molecular medicine · 2022Review
- Endoplasmic Reticulum Stress Contributes to Gefitinib-Induced Apoptosis in Glioma.International journal of molecular sciences · 2021Article
- Small molecules restore the function of mutant CLC5 associated with Dent disease.Journal of cellular and molecular medicine · 2021Article
- Swainsonine Triggers ParaptosisFrontiers in pharmacology · 2021Article
- Vitamin BBiomolecules · 2020Article
- Cumingianoside A, a Phyto-Triterpenoid Saponin Inhibits Acquired BRAF Inhibitor Resistant Melanoma Growth via Programmed Cell Death.Frontiers in pharmacology · 2019Article
- The role of the unfolded protein response in arrhythmias.Channels (Austin, Tex.) · 2018Review
- The unfolded protein response impacts melanoma progression by enhancing FGF expression and can be antagonized by a chemical chaperone.Scientific reports · 2017Article
- Epigallocatechin-3-gallate enhances ER stress-induced cancer cell apoptosis by directly targeting PARP16 activity.Cell death discovery · 2017Article
- Endoplasmic reticulum stress in chondrodysplasias caused by mutations in collagen types II and X.Cell stress & chaperones · 2016Review
- The entangled ER-mitochondrial axis as a potential therapeutic strategy in neurodegeneration: A tangled duo unchained.Cell calcium · 2016Review
- Role for the Unfolded Protein Response in Heart Disease and Cardiac Arrhythmias.International journal of molecular sciences · 2015Review
- Tumor cell survival pathways activated by photodynamic therapy: a molecular basis for pharmacological inhibition strategies.Cancer metastasis reviews · 2015Review
- Endoplasmic reticulum stress-mediated pathways to both apoptosis and autophagy: Significance for melanoma treatment.World journal of experimental medicine · 2015Review
- Inflammation and ER stress downregulate BDH2 expression and dysregulate intracellular iron in macrophages.Journal of immunology research · 2014Article
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Authors and funding
9 authors at 1 institution in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
background and purpose4-Phenylbutyric acid (4-PBA) is a chemical chaperone that eliminates the accumulation of unfolded proteins in the endoplasmic reticulum (ER). However, its chaperoning ability is often weak and unable to attenuate the unfolded protein response (UPR) in vitro or in vivo. To develop more potent chemical chaperones, we synthesized six analogues of 4-PBA and evaluated their pharmacological actions on the UPR. EXPERIMENTAL APPROACH: NRK-52E cells were treated with ER stress inducers (tunicamycin or thapsigargin) in the presence of each of the 4-PBA analogues; the suppressive effects of these analogues on the UPR were assessed using selective indicators for individual UPR pathways. KEY
results2-POAA-OMe, 2-POAA-NO2 and 2-NOAA, but not others, suppressed the induction of ER stress markers GRP78 and CHOP. This suppressive effect was more potent than that of 4-PBA. Of the three major UPR branches, the IRE1 and ATF6 pathways were markedly blocked by these compounds, as indicated by suppression of XBP1 splicing, inhibition of UPRE and ERSE activation, and inhibition of JNK phosphorylation. Unexpectedly, however, these agents did not inhibit phosphorylation of PERK and eIF2α triggered by ER stress. These compounds dose-dependently inhibited the early activation of NF-κB in ER stress-exposed cells. 2-POAA-OMe and 2-POAA-NO2 also inhibited ER stress-induced phosphorylation of Akt. CONCLUSION AND IMPLICATIONS: The 4-PBA analogues 2-POAA-OMe, 2-POAA-NO2 and 2-NOAA strongly inhibited activation of the IRE1 and ATF6 pathways and downstream pathogenic targets, including NF-κB and Akt, in ER stress-exposed cells. These compounds may be useful for therapeutic intervention in ER stress-related pathological conditions.
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