Imide-Based PROTAC Molecules for Targeted Protein Degradation

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Solution Overview

Problem

Current treatments for diseases like multiple myeloma and cancers face challenges in targeting and modulating certain protein classes, particularly transcription factors, due to non-specific effects and the inability to effectively leverage protein-protein interactions.

Innovation Solution

Development of bifunctional compounds, known as proteolysis targeting chimeric (PROTAC) molecules, which recruit endogenous proteins to E3 Ubiquitin Ligases for degradation, utilizing a cereblon E3 Ubiquitin Ligase binding moiety and a protein targeting moiety to specifically target and degrade proteins, thereby modulating protein levels and activity.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Adaptability or versatility

If small molecules are used to target protein-protein interactions, then the ability to modulate transcription factors and other proteins is improved, but the non-specific effects and inability to effectively leverage protein-protein interactions worsen

Engineering Contradiction:

Improveability to modulate protein classesVSAvoidspecificity of targeting

Core Design Contradiction:

Adaptability or versatilityVSReliability

Solution Approach 1:

The patent employs PROTAC molecules as intermediary compounds that bridge the gap between small molecule drugs and protein targets. These bifunctional molecules contain one end that binds to the target protein and another end that recruits an E3 ubiquitin ligase, acting as a mediator to achieve specific protein degradation without the non-specific effects of traditional small molecules

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The PROTAC molecules are segmented into distinct functional domains: a target-binding moiety, a linker region, and an E3 ligase-recruiting moiety. This segmentation allows each component to perform its specific function independently, enabling precise targeting of protein-protein interactions while maintaining overall molecular stability and efficacy

Inventive Principle:

Principle #1Segmentation

2Ease of operation

If traditional small molecule drugs are used, then the simplicity of administration is maintained, but the effectiveness in targeting transcription factors and modulating protein levels deteriorates

Engineering Contradiction:

Improvesimplicity of administrationVSAvoideffectiveness in modulating protein levels

Core Design Contradiction:

Ease of operationVSProductivity

Solution Approach 1:

The patent replaces the traditional mechanical inhibition mechanism of small molecule drugs with a biochemical degradation mechanism. Instead of merely blocking protein function, PROTAC molecules recruit cellular machinery (E3 ubiquitin ligases and proteasomes) to actively degrade target proteins, significantly enhancing therapeutic effectiveness while maintaining oral administration capability

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

3Reliability

If E3 ubiquitin ligases are targeted to achieve substrate specificity, then the specificity for certain protein substrates is improved, but the challenge in developing ligands that disrupt protein-protein interactions worsens

Engineering Contradiction:

Improvesubstrate specificityVSAvoidcomplexity of ligand development

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent utilizes the universal E3 ubiquitin ligase machinery present in all cells to achieve substrate-specific protein degradation. By designing PROTAC molecules with different target-binding moieties but common E3 ligase-recruiting domains, the approach achieves high substrate specificity while simplifying ligand development through modular design

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

These compounds enable targeted ubiquitination and degradation of a wide range of proteins, offering a broad spectrum of pharmacological activities and effective treatment options for diseases such as multiple myeloma by specifically lowering protein levels in cells.

Implementation Method 1

bifunctional compounds, known as proteolysis targeting chimeric (PROTAC) molecules, which recruit endogenous proteins to E3 Ubiquitin Ligases for degradation

Methodology Applied

Scientific EffectProtein-protein interaction:

Implementation Method 2

These compounds enable targeted ubiquitination and degradation of a wide range of proteins

Methodology Applied

Scientific EffectUbiquitination:

Implementation Method 3

proteolysis targeting chimeric (PROTAC) molecules, which recruit endogenous proteins to E3 Ubiquitin Ligases for degradation

Methodology Applied

Scientific EffectProteolysis:

Data Source

PatentUS20240368179A1Imide-based modulators of proteolysis and methods of use

Publication Date: 2024.11.07 YALE UNIVERSITY

AI summary

The description relates to imide-based compounds, including bifunctional compounds comprising the same, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins which are degraded and/or otherwise inhibited by bifunctional compounds according to the present invention. In particular, the description provides compounds, which contain on one end a ligand which binds to the cereblon E3 ubiquitin ligase and on the other end a moiety which binds a target protein such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. Compounds can be synthesized that exhibit a broad range of pharmacological activities consistent with the degradation/inhibition of targeted polypeptides of nearly any type.