ISRIB Modulator Selective PERK Pathway Inhibition

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Solution Overview

Problem

Current treatments for integrated stress response-associated diseases, particularly those involving eIF2α phosphorylation, lack effective therapeutics that can selectively modulate the PERK/ATF4 pathway without causing global translational attenuation or disrupting protein homeostasis.

Innovation Solution

Development of a compound, ISRIB, which selectively inhibits the PERK signaling pathway by blocking the translational attenuation induced by eIF2α phosphorylation, thereby allowing for the preferential translation of key regulatory molecules like ATF4 while maintaining overall protein synthesis.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If eIF2α is phosphorylated to attenuate global translation during stress response, then protein homeostasis is maintained, but global protein synthesis is reduced

Engineering Contradiction:

Improveprotein homeostasisVSAvoidglobal protein synthesis

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

The compound selectively modulates the PERK/eIF2α pathway to achieve local translational control - allowing preferential translation of specific mRNAs (like ATF4 with uORFs) while maintaining attenuation of global translation. This resolves the contradiction by making translation regulation mRNA-specific rather than uniform across all transcripts

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The invention segments the translation control mechanism by differentiating between mRNAs with uORFs (which are upregulated) and standard mRNAs (which are attenuated). The compound enhances this segmentation by selectively affecting the PERK pathway's impact on different mRNA populations, allowing simultaneous protein homeostasis maintenance and selective protein synthesis

Inventive Principle:

Principle #1Segmentation

2Productivity

If PERK signaling is inhibited to prevent translational attenuation, then global protein synthesis is maintained, but selective translation of regulatory molecules like ATF4 is disrupted

Engineering Contradiction:

Improveglobal protein synthesisVSAvoidselective translation of regulatory molecules

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The compound acts as an intermediary that modulates the interaction between phosphorylated eIF2α and eIF2B. Instead of directly inhibiting PERK or eIF2α phosphorylation, it interferes with the competitive binding between p-eIF2α and eIF2B, thereby fine-tuning the availability of the eIF2-GTP-Met-tRNAi ternary complex for selective mRNAs while maintaining overall translational control

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The compound changes the kinetic parameters of eIF2B activity by affecting the dissociation rate of phosphorylated eIF2 from eIF2B. This parameter change allows the system to maintain sufficient ternary complex formation for global protein synthesis while preserving the selective translation mechanism for regulatory mRNAs through uORF-mediated control

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentEP2968347B1Modulators of the eif2alpha pathway

Publication Date: 2023.08.02 RGT UNIV OF CALIFORNIA

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Figure 2a~2b

AI summary

Provided herein, inter alia, are compounds and methods useful for modulating the translational effects of eIF2 phosphorylation, the Integrated Stress Response (ISR), and the unfolded protein response (UPR); for treating diseases; for increasing protein production, and for improving long-term memory.