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

Area of Science:

• Molecular Biology
• Pharmacology
• Cellular Biology

Background:

• The unfolded protein response (UPR) pathway, particularly the IRE1/XBP1s signaling arm, is a promising therapeutic target for various diseases.
• Existing selective activators of IRE1/XBP1s signaling, like IXA4, have limited tissue distribution, restricting their in vivo utility.
• There is a need for novel compounds with enhanced tissue penetration to effectively study and target the IRE1/XBP1s pathway in vivo.

Purpose of the Study:

• To identify and characterize novel selective activators of IRE1/XBP1s signaling with improved tissue activity compared to IXA4.
• To evaluate the efficacy of newly identified compounds in cellular and in vivo models.
• To expand the pharmacological tools available for interrogating the biological and therapeutic roles of IRE1/XBP1s signaling.

Main Methods:

• Re-analysis of high-throughput screening hits for compounds with novel structural classes.
• Global RNA sequencing (RNAseq) to confirm transcriptome-wide selectivity for IRE1/XBP1s activation.
• Functional profiling in cell-based assays (e.g., Aβ secretion, insulin secretion) and in vivo mouse models (oral and intraperitoneal dosing).

Main Results:

• Compound IXA62 was identified as a selective IRE1/XBP1s activator.
• IXA62 demonstrated efficacy in cellular assays, reducing Aβ secretion and enhancing insulin secretion.
• In vivo studies showed IXA62 robustly activated IRE1/XBP1s signaling in mouse liver and exhibited broader tissue activity (kidney, lung) compared to IXA4.

Conclusions:

• IXA62 is a potent and selective activator of IRE1/XBP1s signaling with enhanced tissue distribution.
• This compound represents a valuable pharmacological tool for in vivo studies of the IRE1/XBP1s pathway.
• IXA62's properties facilitate further investigation into the therapeutic potential of enhancing adaptive IRE1/XBP1s signaling in diverse diseases.