Sulfur-Bonded E3 Ligase Ligand for PROTAC Protein Degradation

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Solution Overview

Problem

Current E3 Cereblon (CRBN) ligands, such as thalidomide, pomalidomide, and lenalidomide, are covalently bonded to linking units through carbon-nitrogen bonds, with no reports of bonds through carbon-sulfur bonds, limiting the study of heteroatom E3 ubiquitinated ligase ligands and their therapeutic potential.

Innovation Solution

Design and application of a new sulfur-containing E3 ligase ligand in PROTAD small molecule drugs, which forms a ternary complex with a small molecule binder and an E3 ubiquitination ligase, facilitating the degradation of target proteins through ubiquitination.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Adaptability or versatility

If traditional carbon-nitrogen bonded E3 ligase ligands are used, then the ligand structure is well-established, but the ability to study heteroatom E3 ubiquitinated ligase ligands and their therapeutic potential is limited

Engineering Contradiction:

Improveability to study heteroatom E3 ubiquitinated ligase ligandsVSAvoidlack of reported carbon-sulfur bonded structures

Core Design Contradiction:

Adaptability or versatilityVSEase of manufacture

Solution Approach 1:

The patent changes the chemical bonding parameter from carbon-nitrogen to carbon-sulfur bonds in the E3 ligase ligand structure. This parameter change enables the study of heteroatom E3 ubiquitinated ligase ligands while maintaining the functional integrity of the PROTAD compound, thereby improving adaptability without significantly complicating the manufacturing process.

Inventive Principle:

Principle #35Parameter changes

2Adaptability or versatility

If sulfur-containing E3 ligase ligand is designed, then heteroatom E3 ubiquitinated ligase ligase binding ability can be studied, but the structural complexity increases compared to traditional ligands

Engineering Contradiction:

Improvebinding ability study of heteroatom E3 ubiquitinated ligase ligaseVSAvoidstructural complexity of sulfur-containing ligand

Core Design Contradiction:

Adaptability or versatilityVSDevice complexity

Solution Approach 1:

The PROTAD compound is segmented into three distinct functional modules: the small molecule binder (SMBP), the linker (LIN), and the E3 ligase ligand (ULM). This segmentation allows the sulfur-containing E3 ligase ligand to be studied independently while maintaining the overall structural organization, thereby managing complexity through modular design.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent uses the linker (LIN) as an intermediary component that connects the small molecule binder to the sulfur-containing E3 ligase ligand. This intermediary structure facilitates the study of heteroatom E3 ubiquitinated ligase ligase binding ability while maintaining structural stability and reducing the direct complexity between the binder and the modified ligand.

Inventive Principle:

Principle #24Intermediary (Mediator)

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 sulfur-containing E3 ligase ligand effectively degrades target proteins such as BCR-ABL and c-ABL, demonstrating enhanced proteasomal degradation compared to traditional carbon-nitrogen bonded ligands.

Implementation Method 1

the target protein is connected to the E3 ubiquitination ligase through the PROTAD small molecule, and ubiquitinated by the E3 ligase, thereby being degraded under the action of the proteasome

Methodology Applied

Scientific EffectUbiquitination: Chemical Bonding

Implementation Method 2

ubiquitinated by the E3 ligase, thereby being degraded under the action of the proteasome

Methodology Applied

Scientific EffectProteasomal degradation: Decomposition (biological)

Data Source

PatentUS20250064837A1Target protein degradation compounds, their Anti-tumor use, their intermediates and use of intermediates

Publication Date: 2025.02.27 SHANGHAI TECH UNIV

AI summary

The present disclosure relates to compounds of formula (I) and their anti-tumor uses, and their intermediates of formula (III), and uses of the intermediates. The compound of formula (I) has a degrading effect on a specific target protein, which is mainly composed of three parts. The first part is a small molecule compound (SMBP, Small Molecules Binding Protein) that can bind to a protein, the second part LIN is a linker, and the three-part ULM is a ubiquitin ligand (ULM, Ubiquitin Ligase Binding Moiety), wherein SMBP is covalently bound to LIN, and LIN is covalently bound to ULM. A series of compounds designed and synthesized in the present disclosure have a wide range of pharmacological activities, including the functions of degrading specific proteins and/or inhibiting activities of specific proteins, and thus can be used in related tumor treatments.