eIF2B Modulators Attenuate Integrated Stress Response

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Solution Overview

Problem

Current treatments for neurodegenerative diseases, leukodystrophies, cancer, inflammatory diseases, musculoskeletal diseases, and metabolic diseases often fail to effectively modulate the integrated stress response (ISR) pathway, particularly the eIF2α phosphorylation and eIF2B activity, which are crucial for cellular stress management and protein synthesis regulation.

Innovation Solution

The development of compounds, such as those represented by Formula (I), which act as eIF2B modulators, specifically activating eIF2B and attenuating the ISR signaling pathway. These compounds can be used to treat various diseases by enhancing eIF2B activity and reducing the impact of eIF2α phosphorylation.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If eIF2α is phosphorylated in response to stress signals, then cellular stress response is activated, but translation initiation is attenuated

Engineering Contradiction:

Improvestress response activationVSAvoidtranslation initiation

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

The patent introduces ISRIB compounds as intermediary molecules that bind to eIF2B and prevent phosphorylated eIF2α from inhibiting the GEF activity. This mediator resolves the contradiction by allowing stress signaling to occur while maintaining translation initiation capability through competitive binding at the eIF2B interface

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The invention changes the binding affinity parameters of eIF2B by introducing ISRIB compounds that increase the stability of the eIF2B-dimer conformation. This parameter change allows the system to maintain GEF activity despite phosphorylation events, effectively decoupling stress response activation from translation inhibition

Inventive Principle:

Principle #35Parameter changes

2Productivity

If eIF2B activity is enhanced to maintain translation, then protein synthesis is preserved, but sensitivity to phosphorylated eIF2α increases

Engineering Contradiction:

Improveprotein synthesisVSAvoidsensitivity to eIF2α phosphorylation

Core Design Contradiction:

ProductivityVSObject-affected harmful factors

Solution Approach 1:

The patent applies prior cushioning by pre-binding ISRIB compounds to eIF2B before phosphorylated eIF2α can exert its inhibitory effect. This protective binding creates a buffer that cushions against the harmful effects of phosphorylation, allowing eIF2B to maintain GEF activity and support protein synthesis even in stressed conditions

Inventive Principle:

Principle #11Beforehand cushioning (Prior cushioning)

3Reliability

If current treatments are used for neurodegenerative diseases, then general disease management is provided, but effective modulation of ISR pathway is not achieved

Engineering Contradiction:

Improvedisease managementVSAvoidISR pathway modulation

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent introduces ISRIB compounds as specific intermediary molecules that target the eIF2B-eIF2α interface, providing adaptability to modulate the ISR pathway. This intermediary approach allows selective modulation of stress response signaling without broadly affecting other cellular processes, achieving both reliable disease management and pathway-specific adaptability

Inventive Principle:

Principle #24Intermediary (Mediator)

Data Source

PatentUS20250115563A1Modulators of the integrated stress pathway

Publication Date: 2025.04.10 CALICO LIFE SCI LLC

AI summary

Provided herein are compounds, compositions, and methods useful for modulating the integrated stress response (ISR) and for treating related diseases; disorders and conditions.