eIF2B Modulators That Limit Stress Granule Formation

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Solution Overview

Problem

Neurodegenerative diseases such as Parkinson's disease, amyotrophic lateral sclerosis (ALS), Alzheimer's disease, and frontotemporal dementia are characterized by aberrant activation of the integrated stress response pathway involving eukaryotic initiation factor 2B, leading to stress granule formation and neurodegeneration, for which there is a lack of effective therapeutic interventions.

Innovation Solution

Development of small molecule modulators that target eukaryotic initiation factor 2B to modulate its activity, enhance guanine nucleotide exchange, promote dimer formation, and inhibit the integrated stress response pathway, thereby reducing stress granule formation and neurodegeneration.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If eukaryotic initiation factor 2B activity is inhibited through phosphorylation of eukaryotic initiation factor 2, then the integrated stress response pathway is activated leading to stress granule formation, but this causes neurodegeneration in neurodegenerative diseases

Engineering Contradiction:

Improvestress response regulationVSAvoidneurodegeneration

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent uses small molecule compounds as intermediaries to modulate eIF2B activity. These compounds bind to eIF2B and regulate its guanine nucleotide exchange activity, acting as a mediator between the stress signal and the translation initiation process, thereby preventing pathological stress granule formation while maintaining appropriate stress response

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent changes the activity parameter of eIF2B by using modulators that can increase or decrease its guanine nucleotide exchange activity. By adjusting this parameter, the therapy can prevent aberrant activation of the ISR pathway and stress granule formation in neurodegenerative diseases while maintaining physiological stress response capability

Inventive Principle:

Principle #35Parameter changes

2Reliability

If eukaryotic initiation factor 2B guanine nucleotide exchange activity is reduced in VWM/CACH patients, then white matter lesions deteriorate and neurological disorders are exacerbated after stresses, but increasing activity may disrupt normal stress response regulation

Engineering Contradiction:

Improveneurological stabilityVSAvoidstress response flexibility

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent employs dynamic modulators of eIF2B that can adjust their activity based on cellular conditions. The small molecule compounds can modulate eIF2B activity in a controlled manner, allowing the system to adapt to different stress conditions while maintaining neurological stability in VWM/CACH patients

Inventive Principle:

Principle #15Dynamics

Solution Approach 2:

The patent utilizes feedback mechanisms where eIF2B modulators respond to cellular stress signals and adjust eIF2B activity accordingly. This feedback control allows the system to maintain appropriate stress response flexibility while preventing pathological outcomes in neurodegenerative diseases

Inventive Principle:

Principle #23Feedback

Data Source

PatentUS20250388595A1Modulators of eukaryotic initiation factor 2b, compositions and methods

Publication Date: 2025.12.25 DENALI THERAPEUTICS INC

AI summary

The present disclosure relates generally to eukaryotic initiation factor 2B modulators, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or prodrug thereof, and methods of making and using thereof.