Journal of biomolecular screening, 2013-03, Vol.18 (3), p.298-308
2013
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Details
- Autor(en) / Beteiligte
- Titel
- Identification of autophosphorylation inhibitors of the inositol-requiring enzyme 1 alpha (IRE1α) by high-throughput screening using a DELFIA assay
- Ist Teil von
- Journal of biomolecular screening, 2013-03, Vol.18 (3), p.298-308
- Ort / Verlag
- United States
- Erscheinungsjahr
- 2013
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Inositol-requiring enzyme 1 alpha (IRE1α) is a transmembrane sensor protein with both kinase and ribonuclease activity, which plays a crucial role in the unfolded protein response (UPR). Protein misfolding in the endoplasmic reticulum (ER) lumen triggers dimerization and subsequent trans-autophosphorylation of IRE1α. This leads to the activation of its endoribonuclease (RNase) domain and splicing of the mRNA of the transcriptional activator XBP1, ultimately generating an active XBP1 (XBP1s) implicated in multiple myeloma survival. Previously, we have identified human IRE1α as a target for the development of kinase inhibitors that could modulate the UPR in human cells, which has particular relevance for multiple myeloma and other secretory malignancies. Here we describe the development and validation of a 384-well high-throughput screening assay using DELFIA technology that is specific for IRE1α autophosphorylation. Using this format, a focused library of 2312 potential kinase inhibitors was screened, and several novel IRE1α kinase inhibitor scaffolds were identified that could potentially be developed toward new therapies to treat multiple myeloma.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 2472-5552eISSN: 1552-454XDOI: 10.1177/1087057112465647Titel-ID: cdi_crossref_primary_10_1177_1087057112465647
- Format
- –
- Schlagworte
- Animals, Cell Line, Endoribonucleases - antagonists & inhibitors, Endoribonucleases - chemistry, Endoribonucleases - metabolism, High-Throughput Screening Assays - methods, Humans, Insecta, Membrane Proteins - antagonists & inhibitors, Membrane Proteins - metabolism, Multiple Myeloma - drug therapy, Multiple Myeloma - enzymology, Multiple Myeloma - metabolism, Phosphorylation - drug effects, Protein Folding - drug effects, Protein Kinase Inhibitors - chemistry, Protein Kinase Inhibitors - pharmacology, Protein-Serine-Threonine Kinases - antagonists & inhibitors, Protein-Serine-Threonine Kinases - chemistry, Protein-Serine-Threonine Kinases - metabolism, Unfolded Protein Response - drug effects