ISRIB Compounds Modulating eIF2B Activity

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Solution Overview

Problem

Current therapies lack effective modulation of the integrated stress response (ISR) pathway, particularly in addressing diseases associated with impaired eIF2B function.

Innovation Solution

Development of compounds that modulate eIF2B activity, specifically activating eIF2B to attenuate the ISR signaling pathway, using a compound of Formula (I) or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If eIF2α is phosphorylated in response to stress signals, then translation is attenuated to help cells cope with stress, but this blocks ternary complex formation and reduces translation initiation excessively

Engineering Contradiction:

Improvecell stress responseVSAvoidtranslation initiation

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

The patent introduces ISRIB compounds as intermediary molecules that bind to eIF2B and prevent phosphorylated eIF2 from binding to it. This mediator restores ternary complex formation without blocking the stress sensing mechanism, allowing cells to maintain stress response while recovering translation initiation capability.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent modifies the binding parameters of eIF2B by introducing compounds that change its conformational state. ISRIB compounds induce a conformational change in eIF2B that reduces its affinity for phosphorylated eIF2 while maintaining its GEF activity, thereby restoring translation without eliminating stress response.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If eIF2B activity is inhibited to maintain stress response, then cells can cope with stress signals, but translation attenuation becomes excessive and harmful

Engineering Contradiction:

Improvestress signal responseVSAvoidexcessive translation attenuation

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent converts the harmful effect of excessive translation attenuation into a beneficial outcome by using ISRIB compounds to modulate eIF2B activity. The compounds selectively reverse the harmful translation block while preserving the beneficial stress response signaling, effectively converting a pathological state back to a physiological state.

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

3Productivity

If small molecule therapeutics activate eIF2B to restore translation, then translation initiation is improved, but the stress response pathway may be disrupted

Engineering Contradiction:

Improvetranslation initiationVSAvoidISR pathway function

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

Instead of directly stimulating translation initiation or inhibiting eIF2α phosphorylation, the patent inverts the approach by targeting eIF2B activity. The ISRIB compounds bind to eIF2B and induce a conformational change that indirectly restores translation by preventing phosphorylated eIF2 binding, rather than directly activating translation machinery.

Inventive Principle:

Principle #13The other way round (Inversion)

Data Source

PatentUS20250122188A1Modulators of the integrated stress pathway

Publication Date: 2025.04.17 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.