Liver-Targeted PROTAC Composition for Solubility and Permeability

Solution Overview

Problem

PROTAC compounds face challenges in druggability due to high molecular weight, poor solubility, permeability, and off-target toxicity, limiting their effectiveness and safety in targeting specific tissues like the liver.

Innovation Solution

A compound comprising a proteolysis targeting chimera (PROTAC) linked with an asialoglycoprotein receptor (ASGPR) ligand, enhancing solubility and cellular permeability through endocytosis, allowing targeted degradation of proteins in liver tissues.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If PROTAC compounds are designed with high molecular weight to enhance target protein degradation capability, then the degradation efficacy is improved, but the water solubility and cellular permeability deteriorate

Engineering Contradiction:

Improvetarget protein degradation efficacyVSAvoidwater solubility

Core Design Contradiction:

ReliabilityVSQuantity of substance

Solution Approach 1:

The PROTAC compound is segmented into three functional modules: a target protein ligand (LGP), a linker (LK), and an E3 ubiquitin ligase ligand (LGE). This segmentation allows each component to be optimized independently for its specific function while maintaining overall molecular weight within druggable ranges, thereby improving water solubility and cellular permeability without sacrificing degradation efficacy.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The invention creates a composite molecular structure by combining the target protein ligand, linker, and E3 ligase ligand into a single PROTAC molecule. This composite structure integrates multiple functions (target recognition, linker connectivity, and ubiquitin ligase recruitment) into one compound, achieving effective protein degradation while maintaining improved solubility and permeability properties through careful molecular design.

Inventive Principle:

Principle #40Composite materials

2Reliability

If PROTAC compounds are designed with high molecular weight to enhance target protein degradation capability, then the degradation efficacy is improved, but the cellular permeability deteriorates

Engineering Contradiction:

Improvetarget protein degradation efficacyVSAvoidcellular permeability

Core Design Contradiction:

ReliabilityVSEase of operation

Solution Approach 1:

The PROTAC compound is segmented into three functional modules: a target protein ligand (LGP), a linker (LK), and an E3 ubiquitin ligase ligand (LGE). This segmentation allows each component to be optimized independently for its specific function while maintaining overall molecular weight within druggable ranges, thereby improving water solubility and cellular permeability without sacrificing degradation efficacy.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The invention optimizes molecular parameters including molecular weight (maintaining within 500-2000 Da), hydrophobicity (logP values), and structural flexibility through careful selection of linker length and composition. These parameter adjustments enable the PROTAC to achieve adequate cellular permeability while maintaining the molecular complexity needed for effective target protein degradation.

Inventive Principle:

Principle #35Parameter changes

3Adaptability or versatility

If PROTAC compounds are used for broad target coverage, then the versatility is improved, but the off-target toxicity increases

Engineering Contradiction:

Improvetarget coverage rangeVSAvoidoff-target toxicity

Core Design Contradiction:

Adaptability or versatilityVSObject-affected harmful factors

Solution Approach 1:

The invention applies local quality by designing the PROTAC with a highly specific target protein ligand that recognizes a particular disease-related target with high affinity and selectivity. This localized specificity at the binding interface ensures that the PROTAC primarily affects the intended target while minimizing off-target effects, even though the overall molecular structure maintains versatility in recruiting different E3 ligases.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The invention incorporates feedback mechanisms through the ubiquitin-proteasome system, where the PROTAC-induced degradation of the target protein creates a negative feedback loop that limits prolonged or excessive degradation activity. This self-regulating mechanism helps prevent off-target toxicity by naturally terminating the degradation effect once the target protein is depleted, while maintaining versatility in targeting different disease-related proteins.

Inventive Principle:

Principle #23Feedback

4Reliability

If PROTAC compounds are designed with complex structure to enhance degradation mechanism, then the degradation capability is improved, but the druggability deteriorates

Engineering Contradiction:

Improveprotein degradation capabilityVSAvoiddruggability

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The PROTAC compound is segmented into three functional modules: a target protein ligand (LGP), a linker (LK), and an E3 ubiquitin ligase ligand (LGE). This segmentation allows each component to be optimized independently for its specific function while maintaining overall molecular weight within druggable ranges, thereby improving water solubility and cellular permeability without sacrificing degradation efficacy.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The invention optimizes molecular parameters including molecular weight (maintaining within 500-2000 Da), hydrophobicity (logP values), and structural flexibility through careful selection of linker length and composition. These parameter adjustments enable the PROTAC to achieve adequate cellular permeability and manufacturability while maintaining the molecular complexity needed for effective target protein degradation.

Inventive Principle:

Principle #35Parameter changes

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

Improves the druggability and efficacy of PROTACs by enriching in liver tissues, overcoming solubility and permeability issues, and enabling effective protein degradation with reduced off-target effects.

Implementation Method 1

CON is a ligand of an asialoglycoprotein receptor (ASGPR), having a function of enabling the specific tissue targeting function of the PROTAC

Methodology Applied

Scientific EffectReceptor-ligand binding: Absorption (physical)

Implementation Method 2

Ubiquitin-mediated proteolysis is among the most important down regulations of proteins in cells. Ubiquitin-mediated proteolysis pathway can degrade 80% ̃90% of ubiquitinated proteins in cells

Methodology Applied

Scientific EffectUbiquitin-mediated proteolysis: Hydrolysis

Data Source

PatentUS12630579B2Proteolysis targeting compound with tissue targeting capability and use thereof

Publication Date: 2026.05.19 TAI BI DI PHARM TECH SHIJIAZHUANG CO LTD

AI summary

The present invention is based on the discovery of a proteolysis targeting compound having tissue targeting capability and use thereof, relating to medicinal products, and to such a compound or a pharmaceutically acceptable salt thereof, a stereoisomer, a solvate, or a polymorph. The compound is a proteolysis targeting chimera (PROTAC) with specific tissue targeting ability. The compound structure comprises three parts, i.e., A-BD-CON, wherein the part A is a PROTAC, one end of the structure thereof is a target protein ‘binding ligand, and the other end is a ubiquitin ligase ligand; and the part CON is a ligand of an asialoglycoprotein receptor (ASGPR), enabling the specific tissue targeting function. The compound enriches in liver tissue and is able to target cells in the tissue. The invention achieves improved druggability of the PROTAC with higher solubility and cellular membrane permeability, therefore produces enhanced pharmaceutical effect on the specific target tissue.