Ire1 Modulators for Protein Folding Capacity Control
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Solution Overview
Problem
Current technologies lack effective means to pharmacologically modulate the protein-folding capacity of cells and prevent unfolded protein response (UPR)-induced cell death, which is implicated in various diseases such as cancer, diabetes, and neurodegenerative disorders.
Innovation Solution
Development of small molecule Ire1 activators and modulators that can increase or decrease the protein-folding capacity of cells by targeting the Ire1 kinase-ribonuclease domain, along with methods to screen for and detect these modulators, including using sunitinib as a reference compound.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If small molecule Ire1 modulators are developed to regulate protein folding capacity, then cellular protein-folding capacity can be modulated, but no effective pharmacological means existed before this invention
Solution Approach 1:
The patent introduces small molecule compounds as intermediary substances that bind to the Ire1 kinase-ribonuclease domain to modulate its activity. These small molecules serve as pharmacological mediators between external treatment and cellular protein-folding capacity, enabling reliable control of the UPR pathway without requiring genetic manipulation or complex delivery systems.
Solution Approach 2:
The invention changes the activity state of Ire1 through small molecule binding, effectively modulating parameters such as kinase activity, ribonuclease activity, and oligomerization state. This allows dynamic control of protein-folding capacity by altering the functional parameters of Ire1 in response to cellular stress conditions.
2Reliability
If Ire1 activators are used to increase protein-folding capacity, then cells can handle misfolded proteins better, but UPR-induced cell death may be exacerbated in certain disease contexts
Solution Approach 1:
The patent develops both activators and inhibitors of Ire1, enabling dynamic adjustment of UPR activity based on cellular needs. The small molecule modulators can shift Ire1 activity along a continuum rather than fixed activation states, allowing optimization of protein-folding capacity while avoiding excessive activation that would trigger apoptosis in disease contexts like cancer or neurodegenerative disorders.
Solution Approach 2:
By changing the activity parameters of Ire1 through small molecule binding, the invention can tune the UPR response to appropriate levels. This parameter control allows sufficient activation to enhance protein folding in stressed cells while preventing overactivation that would lead to harmful cell death, particularly important in cancers where UPR supports tumor survival.
3Productivity
If screening methods for Ire1 modulators are developed, then compound identification becomes possible, but detection and measurement of Ire1 activity presents technical challenges
Solution Approach 1:
The patent extracts and utilizes the ribonuclease activity of Ire1 as a measurable output signal in screening assays. By focusing on the cleavage of specific RNA substrates (such as HAC1 or XBP1 pre-mRNA) as a readout of Ire1 activation, the invention creates a detectable endpoint that can be easily measured using standard molecular biology techniques like RT-PCR or gel electrophoresis, thereby simplifying high-throughput screening.
Solution Approach 2:
The invention replaces direct measurement of complex kinase-ribonuclease domain interactions with a simplified RNA cleavage assay. Instead of attempting to measure multiple conformational changes and protein-protein interactions, the system uses the final RNA cleavage product as a binary readout, substituting a complex mechanical measurement system with a simpler biochemical endpoint that is easier to detect and quantify in high-throughput formats.
Data Source
AI summary
Disclosed herein are, inter alia, compositions for modulating Ire1, Src, or Abl, methods for identifying modulating activity in test compounds, and methods for treating diseases caused by the activity or inactivity of Ire1, Src, or Abl.