Macrocyclic EGFR Degradation Compounds for C797S Drug Resistance

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Solution Overview

Problem

Current EGFR inhibitors, such as Gefitinib, Erlotinib, Afatinib, and Osimertinib, face challenges with drug resistance due to secondary mutations like T790M and C797S, leading to limited efficacy in treating non-small cell lung cancer, with no effective single inhibitor available for EGFR C797S mutation.

Innovation Solution

Development of compounds that inhibit EGFR kinase or induce EGFR degradation through the ubiquitin-proteasome pathway, utilizing macrocyclic compounds of general formula (I) to target and degrade EGFR, potentially overcoming drug resistance.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current EGFR inhibitors (Gefitinib, Erlotinib, Afatinib, Osimertinib) are used to treat non-small cell lung cancer, then tumor cell proliferation is inhibited and apoptosis is promoted, but drug resistance develops due to secondary mutations (T790M, C797S)

Engineering Contradiction:

Improveefficacy of EGFR inhibitorVSAvoidduration of drug effectiveness

Core Design Contradiction:

ReliabilityVSDuration of action of moving object

Solution Approach 1:

The patent changes the mechanism of action parameter from reversible/irreversible binding to inducing protein degradation. The macrocyclic compounds induce EGFR degradation through the ubiquitin-proteasome pathway, fundamentally changing how the drug interacts with the target to overcome resistance caused by parameter changes in the target protein (mutations).

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent replaces the mechanical binding mechanism (competitive binding to kinase domain) with a biochemical degradation mechanism (ubiquitin-proteasome pathway). This substitution allows the drug to eliminate the target protein entirely rather than just blocking its activity, effectively overcoming resistance to traditional inhibitors.

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

2Reliability

If Osimertinib is used to overcome T790M resistance, then drug resistance caused by T790M is overcome, but new resistance develops due to C797S mutation

Engineering Contradiction:

Improveefficacy against T790M mutationVSAvoideffectiveness against multiple mutations

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The macrocyclic compounds possess universal activity against multiple EGFR mutation types (T790M, C797S, and other resistant mutations) by inducing protein degradation rather than relying on specific binding to mutant configurations. This multi-functional approach allows a single compound to address diverse resistance mechanisms.

Inventive Principle:

Principle #6Universality (Multi-functionality)

Solution Approach 2:

The patent extracts the target protein (EGFR) from the system through induced degradation, removing it entirely rather than attempting to bind to various mutant forms. This extraction approach bypasses the need to adapt to different mutation configurations, providing universal effectiveness against multiple resistance types.

Inventive Principle:

Principle #2Taking out (Extraction)

3Power

If Afatinib is used as an irreversible EGFR inhibitor, then potency against EGFR is increased, but selectivity to wild-type EGFR is lost and toxicity increases

Engineering Contradiction:

Improveinhibitory potency of EGFR inhibitorVSAvoidtoxicity of EGFR inhibitor

Core Design Contradiction:

PowerVSObject-affected harmful factors

Solution Approach 1:

The patent applies local quality by targeting specific degradation pathways (ubiquitin-proteasome system) for EGFR while maintaining selectivity. The macrocyclic compounds are designed to induce degradation of mutant EGFR through specific molecular interactions that distinguish mutant from wild-type, allowing potent local action on the target while preserving selectivity and reducing off-target toxicity.

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 compounds effectively inhibit EGFR kinase and induce EGFR degradation, offering a potential solution to drug resistance in non-small cell lung cancer, particularly for mutations like C797S, providing a new therapeutic approach.

Implementation Method 1

inhibit the activation of tyrosine kinases, thereby blocking the EGFR signaling pathway

Methodology Applied

Scientific EffectKinase inhibition: Enzyme

Implementation Method 2

Inducing the degradation of EGFR through the intracellular ubiquitin-proteasome pathway provides a new idea for the treatment of non-small cell lung cancer

Methodology Applied

Scientific EffectUbiquitin-proteasome degradation: Decomposition (biological)

Data Source

PatentEP4079735B1Macrocyclic compounds for inhibiting and inducing degradation of EGFR kinase in the treatment of cancer

Publication Date: 2025.08.06 BEIJING TIDE PHARMACEUTICAL CO LTD

Figure 1

AI summary

Provided is an EGFR kinase inhibitor according to general formula (I) and a pharmaceutical composition containing the inhibitor. The invention can be used to treat diseases related to EGFR kinase, such as cancer. Also provided is a preparation and use of the above inhibitor.