UPR Modulators Reduce ER Stress CHOP for Hearing Loss

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

Noise-induced hearing loss (NIHL) and drug-induced hearing loss pose significant public health challenges, with current interventions failing to effectively address the underlying mechanisms of hearing loss, particularly those mediated by endoplasmic reticulum (ER) stress and the unfolded protein response (UPR).

Innovation Solution

The development of novel compounds, specifically those of Formula I and its pharmaceutically acceptable salts, solvates, or hydrates, which modulate the UPR by reducing the ER stress marker CHOP in thapsigargin-treated HEK 293 cells, thereby offering a therapeutic approach to treating various forms of hearing loss.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current interventions are used to treat hearing loss, then hearing loss symptoms may be addressed, but the underlying mechanisms mediated by ER stress and UPR are not effectively addressed

Engineering Contradiction:

Improveeffectiveness of interventionVSAvoidmechanism targeting capability

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent modifies the UPR signaling pathway by changing the phosphorylation state of eIF2α through administration of compounds that inhibit PERK activation. This parameter change in the UPR pathway leads to reduced CHOP expression and mitigates hearing loss, thereby resolving the contradiction between current intervention effectiveness and mechanism targeting capability.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If UPR modulation is implemented to treat hearing loss, then hearing loss conditions can be mitigated, but ER stress markers such as CHOP remain elevated

Engineering Contradiction:

Improvehearing loss mitigationVSAvoidER stress marker reduction

Core Design Contradiction:

ReliabilityVSMeasurement precision

Solution Approach 1:

The patent employs a feedback mechanism where PERK inhibition leads to reduced eIF2α phosphorylation, which in turn reduces CHOP expression and UPR activation. This feedback loop allows the system to mitigate hearing loss while progressively reducing ER stress markers, resolving the contradiction between hearing loss mitigation and ER stress marker reduction.

Inventive Principle:

Principle #23Feedback

3Strength

If PERK activation is increased to enhance UPR response, then protein folding capacity is improved, but harmful effects such as apoptosis are amplified

Engineering Contradiction:

Improveprotein folding capacityVSAvoidapoptosis

Core Design Contradiction:

StrengthVSObject-generated harmful factors

Solution Approach 1:

Instead of activating PERK to enhance protein folding capacity, the patent inverts the approach by inhibiting PERK activation. This inversion reduces eIF2α phosphorylation and CHOP expression, thereby reducing harmful apoptotic effects while still allowing适度的 protein folding through alternative UPR pathways, thus resolving the contradiction between protein folding capacity and apoptosis.

Inventive Principle:

Principle #13The other way round (Inversion)

Data Source

PatentUS20250134871A1UPR modulators to treat hearing loss

Publication Date: 2025.05.01 JACARANDA BIOSCIENCES INC

AI summary

Provided herein are compounds of Formula (I), pharmaceutical compositions thereof, and methods of their use for treating, preventing, or ameliorating hearing loss.