Identification of a Selective Pharmacologic IRE1/XBP1s Activator with Enhanced Tissue Exposure

Activation of the IRE1/XBP1s signaling arm of the unfolded protein response (UPR) has emerged as a promising strategy to mitigate etiologically diverse diseases. Despite this promise, few compounds are available to selectively activate IRE1/XBP1s signaling to probe the biologic and therapeutic implications of this pathway in human disease. Recently, we identified the compound IXA4 as a highly selective activator of protective IRE1/XBP1s signaling. While IXA4 has proven useful for increasing IRE1/XBP1s signaling in cultured cells and mouse liver, the utility of this compound is restricted by its limited activity in Other tissues. To broaden our ability to pharmacologically interrogate the impact of IRE1/XBP1s signaling in vivo, we sought to identify IRE1/XBP1s activators with greater tissue activity than IXA4. We reanalyzed 'hits' from the high throughput screen used to identify IXA4, selecting compounds from structural classes not previously pursued. We then performed global RNAseq to confirm that these compounds showed transcriptome-wide selectivity for IRE1/XBP1s activation. Functional profiling revealed compound IXA62 as a selective IRE1/XBP1s activator that reduced Aβ secretion from CHO^7PA2 cells and enhanced glucose-stimulated Insulin secretion from rat insulinoma cells, mimicking the effects of IXA4 in these assays. IXA62 robustly and selectively activated IRE1/XBP1s signaling in the liver of mice dosed compound intraperitoneally or orally. In treated mice, IXA62 showed broader tissue activity, relative to IXA4, inducing expression of IRE1/XBP1s target genes in additional tissues such as kidney and lung. Collectively, our results designate IXA62 as a selective IRE1/XBP1s signaling activating compound with enhanced tissue activity, which increases our ability to pharmacologically probe the biologic significance and potential therapeutic utility of enhancing adaptive IRE1/XBP1s signaling in vivo.