VHL-Linked PROTAC Compounds for SHP2 Protein Degradation

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Solution Overview

Problem

Current treatments for SHP2-related diseases, particularly cancer, lack effective methods to degrade SHP2 protein, which is a key regulator in various signaling pathways contributing to cancer cell growth and immune evasion.

Innovation Solution

Development of PROTAC compounds, specifically those with a VHL ligand linker, that target and degrade SHP2 protein by acting as a 'SHP2 binding ligand-linker-E3 ligase ligand' chimera, effectively lowering SHP2 activity in cells.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional SHP2 inhibitors (e.g., SHP099) are used to block SHP2 phosphatase activity, then cancer cell growth is inhibited, but the SHP2 protein itself remains present and active through alternative mechanisms

Engineering Contradiction:

ImproveSHP2 inhibition efficacyVSAvoidSHP2 protein persistence

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

Instead of inhibiting SHP2 enzyme activity pharmacologically, the invention inverts the approach by using a PROTAC molecule to recruit the ubiquitin-proteasome system to degrade the SHP2 protein itself, thereby eliminating the target through proteolysis rather than enzymatic inhibition

Inventive Principle:

Principle #13The other way round (Inversion)

Solution Approach 2:

The PROTAC molecule acts as an intermediary that bridges the SHP2 protein and the E3 ubiquitin ligase (VHL), facilitating ubiquitin transfer to SHP2 and subsequent proteasomal degradation, thereby mediating protein destruction without direct enzyme inhibition

Inventive Principle:

Principle #24Intermediary (Mediator)

2Reliability

If CRISPR-Cas9 is used to ablate the SHP2 protein, then tumor growth is inhibited, but the method involves complex genetic modification procedures

Engineering Contradiction:

ImproveSHP2 protein removal efficacyVSAvoidGenetic modification complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The invention replaces the complex mechanical and biological system of CRISPR-Cas9 genome editing with a small molecule PROTAC that achieves the same functional outcome (SHP2 degradation) through a simpler chemical mechanism involving ubiquitin ligase recruitment and proteasomal degradation

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

Solution Approach 2:

The invention changes the approach from permanent genetic modification (CRISPR) to reversible protein degradation (PROTAC), allowing dynamic control of SHP2 levels through pharmacological dosing while achieving similar therapeutic effects with reduced complexity

Inventive Principle:

Principle #35Parameter changes

3Reliability

If PROTAC compounds with VHL ligand linker are designed to degrade SHP2, then SHP2 degradation activity is improved, but the molecular structure becomes more complex

Engineering Contradiction:

ImproveSHP2 degradation activityVSAvoidPROTAC molecular structure

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The PROTAC molecule is segmented into distinct functional modules: an SHP2-binding ligand portion, a linker region, and a VHL E3 ligase ligand portion, allowing each segment to be optimized independently for its specific function while maintaining overall molecular effectiveness

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The PROTAC represents a composite molecular structure combining elements from different functional classes (SHP2 inhibitor scaffold + VHL ligand) into a single hybrid molecule that performs multiple functions: target binding, E3 ligase recruitment, and ubiquitin-mediated degradation

Inventive Principle:

Principle #40Composite materials

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

The PROTAC compounds exhibit excellent SHP2 degradation activity, stability, and physicochemical properties, providing a therapeutic approach to treat or prevent SHP2-related diseases such as cancer by degrading SHP2 and reducing its activity.

Implementation Method 1

The compounds according to the present invention are PROTAC (Proteolysis-targeting chimera) compounds of 'SHP2 binding ligand-linker-E3 ligase ligand'

Methodology Applied

Scientific EffectProteolysis-targeting chimera mechanism:

Implementation Method 2

Ablation of the SHP2 protein may also provide an alternative and perhaps even more effective strategy for inhibiting SHP2 activity

Methodology Applied

Scientific EffectUbiquitination:

Implementation Method 3

it has been demonstrated that SHP2 inactivation by CRISPR-Cas9 induces senescence and inhibits tumor growth in xenograft models

Methodology Applied

Scientific EffectProteasomal degradation:

Data Source

PatentUS20250230154A1Compound having SHP2 protein degrading activity, and medical uses thereof

Publication Date: 2025.07.17 UBIX THERAPEUTICS

AI summary

The present disclosure provides a compound having a specific chemical structure or a pharmaceutically acceptable salt thereof having excellent activity in terms of degrading SHP2. The present disclosure also provides a composition comprising such a compound or a pharmaceutically acceptable salt thereof. The present disclosure also provides a medical use of a compound according to the present disclosure, a salt thereof, and a composition comprising the same for the treatment or prophylaxis of SHP2-related diseases (e.g., cancer). The present disclosure also provides a method for treating or preventing a SHP2-related disease (e.g., cancer) comprising administering to a subject in need thereof an effective amount of a compound according to the present disclosure, a salt thereof, or a composition comprising the same.