Macrocyclic EGFR Inhibitors for Resistant NSCLC and Brain Metastases
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Solution Overview
Problem
Current EGFR tyrosine kinase inhibitors (TKIs) fail to effectively target EGFR mutations such as del19/L858R T790M C797S, leading to rapid disease progression, and existing compounds lack the necessary characteristics for a broad-spectrum inhibitor that can penetrate the blood-brain barrier and reduce off-target toxicity.
Innovation Solution
Development of macrocyclic compounds that inhibit mutant EGFR, including del19/L858R variants with or without T790M and/or C797S mutations, while maintaining selectivity across the human kinome and minimizing wild-type EGFR inhibition, and possessing the ability to penetrate the brain.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current EGFR TKIs are used to treat EGFR mutated NSCLC, then initial tumor response is achieved, but response duration is limited due to rapid development of resistance mutations
Solution Approach 1:
The patent describes EGFR TKIs with preliminary structural design features (specific molecular configurations and substitutions) that preemptively address resistance mechanisms. The compounds are designed with predetermined characteristics that enable them to bind to and inhibit EGFR mutants even before resistance mutations like T790M or C797S develop, thereby extending response duration and improving reliability of sustained tumor control.
Solution Approach 2:
The invention employs parameter changes in the molecular structure of EGFR TKIs, specifically modifying chemical parameters (substitutions at positions R1-R3, A-B ring systems, L linker variations) to alter binding affinity and selectivity profiles. These parameter changes enable the compounds to maintain effective inhibition against multiple EGFR mutant variants (del19, L858R, T790M, C797S) simultaneously, thereby extending response duration and improving treatment reliability.
2Adaptability or versatility
If broad-spectrum EGFR inhibition is achieved to cover multiple resistance mutations, then coverage of resistant variants is improved, but off-target toxicity increases
Solution Approach 1:
The patent applies local quality by designing EGFR TKIs with specific localized molecular features (particular substitutions at R1-R3 positions, specific A-B ring configurations, and tailored L linker properties) that create selective binding pockets. These localized structural qualities enable the compounds to distinguish between mutant EGFR variants and wild-type EGFR, achieving broad coverage of resistant variants while minimizing off-target toxicity through precise local molecular recognition.
Solution Approach 2:
The invention achieves universality by developing EGFR TKIs with multi-functional molecular structures that can simultaneously target multiple EGFR mutant variants (del19, L858R, T790M, C797S) with a single compound. The compounds possess universal binding characteristics through specific structural features (substitutions, ring systems, linker variations) that adapt to different mutant configurations, providing broad-spectrum coverage while maintaining selectivity to reduce off-target effects.
3Adaptability or versatility
If EGFR TKI penetrates the blood-brain barrier to treat brain metastases, then central nervous system efficacy is improved, but off-target effects in the brain may increase
Solution Approach 1:
The patent employs parameter changes in the molecular properties of EGFR TKIs, specifically adjusting lipophilicity, molecular weight, and structural flexibility through variations in R1-R3 substitutions, A-B ring systems, and L linkers. These parameter changes optimize blood-brain barrier penetration capability while controlling off-target effects in the brain by fine-tuning the balance between permeability and selective binding to mutant EGFR in CNS tissues.
Data Source
AI summary
The present invention encompasses compounds of formula (I) wherein the groups R1 to R3, A, B and L and p and q have the meanings given in the claims and specification, their use as inhibitors of mutant EGFR, pharmaceutical compositions which contain compounds of this kind and their use as medicaments/medical uses, especially as agents for treatment and/or prevention of oncological diseases.