eIF2B Modulator Compounds for Stress-Resilient ISR Control

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Solution Overview

Problem

Current therapies are inadequate in modulating the integrated stress response (ISR) pathway, particularly through eIF2B activation, which is crucial for addressing various diseases such as neurodegenerative disorders, leukodystrophies, cancers, inflammatory diseases, and metabolic disorders.

Innovation Solution

Development of compounds and compositions that act as eIF2B modulators, specifically eIF2B activators, represented by Formulas (I) and (II), to attenuate the ISR pathway and treat associated diseases.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If eIF2α is phosphorylated to attenuate translation and cope with stress, then cellular resilience to stress is improved, but sensitivity to harmful stress signals increases

Engineering Contradiction:

Improvecellular resilience to stressVSAvoidsensitivity to harmful stress signals

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent introduces eIF2B activators as intermediary molecules that modulate the ISR pathway. These activators bind to eIF2B and stabilize its dimer conformation, enhancing GEF activity and reducing sensitivity to eIF2α phosphorylation. This intermediary mechanism allows attenuation of the ISR pathway while maintaining cellular resilience, effectively resolving the contradiction between stress adaptation and harmful signal sensitivity.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent employs small molecule compounds (Formulas I and II) that change the functional parameters of eIF2B. By binding to eIF2B and stabilizing its dimer conformation, these compounds increase GEF activity and reduce the cellular response to eIF2α phosphorylation. This parameter modulation enables the system to maintain stress resilience while reducing sensitivity to harmful stress signals.

Inventive Principle:

Principle #35Parameter changes

2Object-affected harmful factors

If eIF2B activity is increased to attenuate ISR pathway, then sensitivity to eIF2α phosphorylation is reduced, but complexity of molecular intervention increases

Engineering Contradiction:

Improvesensitivity to eIF2α phosphorylationVSAvoidcomplexity of molecular intervention

Core Design Contradiction:

Object-affected harmful factorsVSDevice complexity

Solution Approach 1:

The patent utilizes small molecule compounds (Formulas I and II) that modulate eIF2B activity by stabilizing its dimer conformation and enhancing GEF activity. These small molecules provide a straightforward molecular intervention mechanism, avoiding complex therapeutic approaches while effectively reducing sensitivity to eIF2α phosphorylation and attenuating the ISR pathway.

Inventive Principle:

Principle #35Parameter changes

3Adaptability or versatility

If small molecule eIF2B activators are developed to modulate ISR pathway, then therapeutic potential for multiple diseases is improved, but difficulty in achieving selective eIF2B activation increases

Engineering Contradiction:

Improvetherapeutic potential for multiple diseasesVSAvoiddifficulty in achieving selective eIF2B activation

Core Design Contradiction:

Adaptability or versatilityVSDifficulty of detecting and measuring

Solution Approach 1:

The patent designs small molecule compounds with specific structural features (Formulas I and II) that enable selective binding to eIF2B. The molecules contain specific substituents and stereochemical configurations that confer selectivity for eIF2B over other cellular targets. This local quality optimization ensures selective activation of eIF2B, facilitating therapeutic potential across multiple diseases while maintaining specificity.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent develops eIF2B activators that can be applied universally across multiple disease states (neurodegenerative diseases, leukodystrophies, cancers, inflammatory diseases, and metabolic disorders). The small molecule compounds (Formulas I and II) provide a multi-functional therapeutic approach by modulating the ISR pathway in a manner that benefits various disease types, achieving versatility without requiring disease-specific interventions.

Inventive Principle:

Principle #6Universality (Multi-functionality)

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

The eIF2B modulators enhance cellular resilience to stress by stabilizing the eIF2B dimer conformation, reducing the sensitivity to eIF2α phosphorylation, thereby providing therapeutic benefits for neurodegenerative diseases, leukodystrophies, cancers, inflammatory diseases, and metabolic disorders.

Implementation Method 1

eIF2B5 catalyzes the GDP/GTP exchange reaction and, together with a partially homologous subunit eIF2B3, constitutes the 'catalytic core'

Methodology Applied

Scientific EffectGDP/GTP exchange reaction:

Implementation Method 2

The tight and nonproductive binding of phosphorylated eIF2 to eIF2B prevents loading of the eIF2 complex with GTP, thus blocking ternary complex formation and reducing translation initiation

Methodology Applied

Scientific EffectTight binding:

Implementation Method 3

Molecules such as ISRIB interact with and stabilize the eIF2B dimer conformation, thereby enhancing intrinsic GEF activity

Methodology Applied

Scientific EffectConformational stabilization:

Data Source

PatentEP3704091B1Modulators of the integrated stress pathway

Publication Date: 2025.12.31 CALICO LIFE SCI LLC

AI summary

Provided herein are compounds of Formula (I) or Formula (II), compositions, and methods there of useful for modulating the integrated stress response (ISR) and for treating related diseases, disorders and conditions.