Potent and Selective Inhibitors of the Inositol-requiring Enzyme 1 Endoribonuclease*

Inositol-requiring enzyme 1 (IRE1) is the most highly conserved signaling node of the unfolded protein response (UPR) and represents a potential therapeutic target for a number of diseases associated with endoplasmic reticulum stress. IRE1 activates the XBP-1 transcription factor by site-specific cl...

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Main Authors:	Volkmann, Kori, Lucas, Julie L., Vuga, Danka, Wang, Xiaoping, Brumm, Duane, Stiles, Caryn, Kriebel, David, Der-Sarkissian, Ani, Krishnan, Kris, Schweitzer, Colleen, Liu, Zheng, Malyankar, Uriel M., Chiovitti, David, Canny, Marella, Durocher, Dan, Sicheri, Frank, Patterson, John B.
Format:	Online
Language:	English
Published:	American Society for Biochemistry and Molecular Biology 2011
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3069474/

id	pubmed-3069474
recordtype	oai_dc
spelling	pubmed-30694742011-04-07 Potent and Selective Inhibitors of the Inositol-requiring Enzyme 1 Endoribonuclease* Volkmann, Kori Lucas, Julie L. Vuga, Danka Wang, Xiaoping Brumm, Duane Stiles, Caryn Kriebel, David Der-Sarkissian, Ani Krishnan, Kris Schweitzer, Colleen Liu, Zheng Malyankar, Uriel M. Chiovitti, David Canny, Marella Durocher, Dan Sicheri, Frank Patterson, John B. RNA Inositol-requiring enzyme 1 (IRE1) is the most highly conserved signaling node of the unfolded protein response (UPR) and represents a potential therapeutic target for a number of diseases associated with endoplasmic reticulum stress. IRE1 activates the XBP-1 transcription factor by site-specific cleavage of two hairpin loops within its mRNA to facilitate its nonconventional splicing and alternative translation. We screened for inhibitors using a construct containing the unique cytosolic kinase and endoribonuclease domains of human IRE1α (hIRE1α-cyto) and a mini-XBP-1 stem-loop RNA as the substrate. One class compounds was salicylaldehyde analogs from the hydrolyzed product of salicylaldimines in the library. Salicylaldehyde analogs were active in inhibiting the site-specific cleavage of several mini-XBP-1 stem-loop RNAs in a dose-dependent manner. Salicyaldehyde analogs were also active in inhibiting yeast Ire1 but had little activity inhibiting RNase L or the unrelated RNases A and T1. Kinetic analysis revealed that one potent salicylaldehyde analog, 3-ethoxy-5,6-dibromosalicylaldehyde, is a non-competitive inhibitor with respect to the XBP-1 RNA substrate. Surface plasmon resonance studies confirmed this compound bound to IRE1 in a specific, reversible and dose-dependent manner. Salicylaldehydes inhibited XBP-1 splicing induced pharmacologically in human cells. These compounds also blocked transcriptional up-regulation of known XBP-1 targets as well as mRNAs targeted for degradation by IRE1. Finally, the salicylaldehyde analog 3-methoxy-6-bromosalicylaldehyde strongly inhibited XBP-1 splicing in an in vivo model of acute endoplasmic reticulum stress. To our knowledge, salicylaldehyde analogs are the first reported specific IRE1 endoribonuclease inhibitors. American Society for Biochemistry and Molecular Biology 2011-04-08 2011-02-08 /pmc/articles/PMC3069474/ /pubmed/21303903 http://dx.doi.org/10.1074/jbc.M110.199737 Text en © 2011 by The American Society for Biochemistry and Molecular Biology, Inc. Author's Choice—Final version full access. Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) applies to Author Choice Articles
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Volkmann, Kori Lucas, Julie L. Vuga, Danka Wang, Xiaoping Brumm, Duane Stiles, Caryn Kriebel, David Der-Sarkissian, Ani Krishnan, Kris Schweitzer, Colleen Liu, Zheng Malyankar, Uriel M. Chiovitti, David Canny, Marella Durocher, Dan Sicheri, Frank Patterson, John B.
spellingShingle	Volkmann, Kori Lucas, Julie L. Vuga, Danka Wang, Xiaoping Brumm, Duane Stiles, Caryn Kriebel, David Der-Sarkissian, Ani Krishnan, Kris Schweitzer, Colleen Liu, Zheng Malyankar, Uriel M. Chiovitti, David Canny, Marella Durocher, Dan Sicheri, Frank Patterson, John B. Potent and Selective Inhibitors of the Inositol-requiring Enzyme 1 Endoribonuclease*
author_facet	Volkmann, Kori Lucas, Julie L. Vuga, Danka Wang, Xiaoping Brumm, Duane Stiles, Caryn Kriebel, David Der-Sarkissian, Ani Krishnan, Kris Schweitzer, Colleen Liu, Zheng Malyankar, Uriel M. Chiovitti, David Canny, Marella Durocher, Dan Sicheri, Frank Patterson, John B.
author_sort	Volkmann, Kori
title	Potent and Selective Inhibitors of the Inositol-requiring Enzyme 1 Endoribonuclease*
title_short	Potent and Selective Inhibitors of the Inositol-requiring Enzyme 1 Endoribonuclease*
title_full	Potent and Selective Inhibitors of the Inositol-requiring Enzyme 1 Endoribonuclease*
title_fullStr	Potent and Selective Inhibitors of the Inositol-requiring Enzyme 1 Endoribonuclease*
title_full_unstemmed	Potent and Selective Inhibitors of the Inositol-requiring Enzyme 1 Endoribonuclease*
title_sort	potent and selective inhibitors of the inositol-requiring enzyme 1 endoribonuclease*
description	Inositol-requiring enzyme 1 (IRE1) is the most highly conserved signaling node of the unfolded protein response (UPR) and represents a potential therapeutic target for a number of diseases associated with endoplasmic reticulum stress. IRE1 activates the XBP-1 transcription factor by site-specific cleavage of two hairpin loops within its mRNA to facilitate its nonconventional splicing and alternative translation. We screened for inhibitors using a construct containing the unique cytosolic kinase and endoribonuclease domains of human IRE1α (hIRE1α-cyto) and a mini-XBP-1 stem-loop RNA as the substrate. One class compounds was salicylaldehyde analogs from the hydrolyzed product of salicylaldimines in the library. Salicylaldehyde analogs were active in inhibiting the site-specific cleavage of several mini-XBP-1 stem-loop RNAs in a dose-dependent manner. Salicyaldehyde analogs were also active in inhibiting yeast Ire1 but had little activity inhibiting RNase L or the unrelated RNases A and T1. Kinetic analysis revealed that one potent salicylaldehyde analog, 3-ethoxy-5,6-dibromosalicylaldehyde, is a non-competitive inhibitor with respect to the XBP-1 RNA substrate. Surface plasmon resonance studies confirmed this compound bound to IRE1 in a specific, reversible and dose-dependent manner. Salicylaldehydes inhibited XBP-1 splicing induced pharmacologically in human cells. These compounds also blocked transcriptional up-regulation of known XBP-1 targets as well as mRNAs targeted for degradation by IRE1. Finally, the salicylaldehyde analog 3-methoxy-6-bromosalicylaldehyde strongly inhibited XBP-1 splicing in an in vivo model of acute endoplasmic reticulum stress. To our knowledge, salicylaldehyde analogs are the first reported specific IRE1 endoribonuclease inhibitors.
publisher	American Society for Biochemistry and Molecular Biology
publishDate	2011
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3069474/
_version_	1611448143647342592

Potent and Selective Inhibitors of the Inositol-requiring Enzyme 1 Endoribonuclease*

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