IRE1 Activating Compounds for Selective Proteostasis
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current IRE1 activating compounds for treating diseases associated with ER stress have off-pathway activity and pleiotropic toxicity due to binding other protein kinases, limiting their utility in pharmacologic IRE1/XBP1s activation.
Innovation Solution
Development of non-toxic, highly-selective compounds that activate the IRE1/XBP1s signaling pathway independently of the IRE1 kinase domain, avoiding binding to the nucleotide-binding pocket and minimizing off-target effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If compounds bind to the IRE1 nucleotide-binding pocket to activate IRE1, then IRE1/XBP1s signaling is activated, but off-pathway activity and pleiotropic toxicity occur due to binding other protein kinases
Solution Approach 1:
The patent applies local quality by designing compounds with specific structural features that selectively interact with the IRE1 nucleotide-binding pocket while avoiding binding to other protein kinases. The compounds exhibit selective binding characteristics that localise their activity to the IRE1 pathway, preventing off-pathway effects and pleiotropic toxicity while maintaining reliable IRE1 activation.
2Productivity
If existing IRE1 activating compounds are used to treat ER stress-related diseases, then therapeutic effect is achieved, but toxicity limits their clinical utility
Solution Approach 1:
The patent applies parameter changes by modifying the chemical and pharmacological parameters of IRE1 activation. The new compounds exhibit improved pharmacokinetic properties, reduced off-target binding, and optimized potency that maintain therapeutic efficacy while minimizing toxicity. These parameter optimizations enable safer clinical translation compared to existing activators.
3Reliability
If IRE1 is activated to promote adaptive ER proteostasis remodeling, then cellular survival is enhanced, but prolonged activation can induce pro-apoptotic response
Solution Approach 1:
The patent applies partial action by developing compounds that provide sufficient IRE1 activation to achieve adaptive proteostasis remodeling and cellular survival without causing excessive or prolonged activation that would trigger pro-apoptotic responses. The compounds exhibit optimized potency and duration of action that strike the right balance between protective and harmful effects.
Data Source
AI summary
Disclosed herein are compounds, their pharmaceutical salts, and pharmaceutical compositions that selectively activate the inositol-requiring enzyme 1 (IRE1)/X-box binding protein 1 (XBP1s) signaling pathway of the unfolded protein response (UPR), but that do not target the IRE1 kinase domain. The compounds are useful in treating diseases or conditions characterized by imbalances in proteostasis within the endoplasmic reticulum (ER) or secretory pathway, including those not associated with ER stress or activation of UPR.