β-Eliminative Conjugation Linkers for Aza-Michael Suppression

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Solution Overview

Problem

Existing β-eliminative linkers for drug conjugates suffer from undesired aza-Michael addition reactions, particularly under physiological conditions, leading to uncontrolled drug release and linker residue activation.

Innovation Solution

Incorporation of a geminally-substituted carbon adjacent to the leaving oxygen in the linker structure to suppress nucleophile addition, reducing the equilibrium constant and rate of undesired reactions.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If β-eliminative linkers are used for drug conjugation, then controlled drug release is achieved, but undesired aza-Michael addition reactions occur leading to uncontrolled drug release

Engineering Contradiction:

Improvecontrolled drug releaseVSAvoidaza-Michael addition reaction

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent applies preliminary anti-action by introducing a geminally-substituted carbon adjacent to the leaving oxygen in the linker structure. This structural modification pre-establishes steric hindrance that counteracts the formation of the undesired aza-Michael addition adduct before the harmful reaction can proceed, thereby suppressing the harmful factor while preserving the beneficial controlled release function

Inventive Principle:

Principle #9Preliminary anti-action

Solution Approach 2:

The patent changes the chemical structure parameter of the linker by incorporating a geminally-substituted carbon (carbon with two identical substituents, typically methyl groups) at the gamma position relative to the leaving oxygen. This structural parameter change increases steric hindrance and reduces the electrophilicity of the beta-carbon, thereby suppressing nucleophilic addition while maintaining the beta-elimination pathway for controlled drug release

Inventive Principle:

Principle #35Parameter changes

2Object-generated harmful factors

If alkyl groups are added to suppress aza-Michael addition, then undesired reactions are reduced, but linker structure complexity increases

Engineering Contradiction:

Improvenucleophile additionVSAvoidlinker structure

Core Design Contradiction:

Object-generated harmful factorsVSDevice complexity

Solution Approach 1:

The patent applies local quality by placing the geminally-substituted carbon at a specific location (gamma position) relative to the leaving oxygen, rather than adding alkyl groups throughout the entire linker structure. This localized modification provides the necessary steric hindrance and electronic effects to suppress nucleophilic addition while minimizing the overall complexity and maintaining the linker's conjugation capabilities

Inventive Principle:

Principle #3Local quality

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 new linkers effectively inhibit aza-Michael addition, ensuring controlled drug release and minimizing unwanted side reactions, thereby enhancing the stability and efficacy of drug conjugates.

Implementation Method 1

β-eliminative linkers, which allow drug release through a rate-controlled, beta-elimination mechanism

Methodology Applied

Scientific EffectBeta-elimination:

Implementation Method 2

such aza-Michael addition occurs at least in an in vitro setting

Methodology Applied

Scientific EffectAza-Michael addition:

Data Source

PatentUS12364771B2Conjugation linkers

Publication Date: 2025.07.22 PROLYNX LLC

AI summary

Provided are β-eliminative linkers suitable for the conjugation of small molecule, peptide, and protein and compounds comprising the linkers.