Pan-YTH Inhibitor N-7 Targets m6A RNA Readers

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Solution Overview

Problem

Current methods for inhibiting YTH domain-containing proteins, which recognize m6A-modified transcripts, lack specificity and efficiency, particularly in targeting multiple YTH domains without reducing protein production levels.

Innovation Solution

Development of a small molecule inhibitor, N-7, which is a pan-inhibitor capable of inhibiting multiple YTH domains from human YTHDF1, YTHDF2, YTHDF3, YTHDC1, and YTHDC2 proteins, with IC50 ranges of 30-48 μM, as characterized by fluorescence polarization competition assays and thermal shift assays.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If RNA-based reagents are used to target YTH domain expression, then protein levels are reduced, but specificity and efficiency in targeting multiple YTH domains remain challenging

Engineering Contradiction:

Improvespecificity of targetingVSAvoidcomplexity of targeting multiple YTH domains

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent applies universality by designing a single small molecule inhibitor (N-7) that can simultaneously target multiple YTH domain-containing proteins (YTHDF1, YTHDF2, YTHDF3, YTHDC1, and YTHDC2). This pan-inhibitor approach eliminates the need for separate RNA-based reagents for each target, resolving the contradiction by providing both broad coverage and specific inhibition through one compound that binds to the conserved YTH domain structure.

Inventive Principle:

Principle #6Universality (Multi-functionality)

2Ease of operation

If traditional genetic manipulation methods are used, then protein function is inhibited, but delivery and temporal control are limited

Engineering Contradiction:

Improveease of deliveryVSAvoidtemporal control precision

Core Design Contradiction:

Ease of operationVSLoss of time

Solution Approach 1:

The patent replaces genetic manipulation methods with a small molecule chemical inhibitor (N-7) that can be delivered systemically and acts rapidly on the YTH domain proteins. This substitution resolves the contradiction by providing easier delivery through conventional pharmacological routes and enabling precise temporal control through dosing regimens, eliminating the delays and complexities associated with genetic transfection and expression.

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

3Reliability

If small molecule inhibitors are developed, then specificity and precision are improved, but few such inhibitors are currently available for YTH-m6A recognition

Engineering Contradiction:

Improvespecificity of inhibitionVSAvoidnumber of available inhibitors

Core Design Contradiction:

ReliabilityVSQuantity of substance

Solution Approach 1:

The patent addresses the scarcity of YTH inhibitors by creating a universal pan-inhibitor (N-7) that targets the conserved YTH domain across multiple protein family members. This single compound expands the available toolset from virtually none to a functional inhibitor with demonstrated activity against all five YTH domain-containing proteins, resolving the contradiction by providing both high specificity and broad coverage simultaneously.

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

N-7 effectively inhibits the interaction between YTH domains and m6A-modified transcripts, offering a precise and potentially therapeutic approach to modulating m6A-related pathways, with demonstrated pan-inhibitory activity across multiple YTH domains.

Implementation Method 1

N-7 is characterized to be a pan-inhibitor in vitro against five YTH domains from human YTHDF1, YTHDF2, YTHDF3, YTHDC1, and YTHDC2 proteins, with IC50 ranges within 30-48 μM measured by the fluorescence polarization competition assay. We demonstrated that N-7 directly interacts with the YTH domain proteins via thermal shift assay.

Methodology Applied

Scientific EffectThermal shift:

Implementation Method 2

Methodology Applied

Scientific EffectFluorescence polarization:

Data Source

PatentUS20250144104A1Discovery of a new inhibitor for the YTH domain-containing m6a RNA readers

Publication Date: 2025.05.08 BOSTON COLLEGE

AI summary

The present invention discloses a method for inhibiting a pan-YTH domain by contacting the pan-YTH domain with a small molecule pan-YTH domain inhibitor. Novel methods of locating the small molecule inhibitors are discussed for high-throughput screening (HTS). The small molecule pan-YTH domain inhibitor is designed to inhibit multiple YTH domains present in a YTH family of proteins that identify m6A-modified transcripts, thereby altering the post-transcriptional modification process.