Acrylamide Derivatives Inhibit Mutant EGFR Exon 20 Insertions
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Solution Overview
Problem
Current EGFR inhibitors are ineffective against mutant EGFR with exon 20 insertions and C797S mutations, leading to limited treatment options for patients with resistant cancers, particularly those with lung adenocarcinoma, where standard therapies result in poor response rates and rapid progression.
Innovation Solution
Development of acrylamide derivatives that specifically inhibit mutant EGFR with exon 20 insertions and C797S mutations, demonstrating high cellular potency and activity in BA/F3 cell lines, thereby blocking proliferation in cancer cells harboring these mutations.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current EGFR inhibitors are used, then treatment of wild-type EGFR is effective, but treatment of mutant EGFR with exon 20 insertions and C797S mutations is ineffective
Solution Approach 1:
The patent modifies the chemical structure of EGFR inhibitors by changing parameters such as introducing acrylamide groups and specific substituent patterns (R1-R7 groups) to alter the binding characteristics of the inhibitor, enabling it to effectively target mutant EGFR variants with exon 20 insertions and C797S mutations that were previously resistant to standard inhibitors
Solution Approach 2:
The invention introduces specific local structural modifications to the inhibitor molecule, including particular substituent groups at defined positions (R1-R7), to create localized interactions that specifically recognize and bind to the unique structural features of mutant EGFR, thereby achieving mutation-specific inhibition
2Duration of action of moving object
If standard EGFR inhibitor therapies are applied, then initial response is achieved, but resistance develops rapidly leading to poor long-term outcomes
Solution Approach 1:
The patent employs inhibitors with pre-designed structural features (acrylamide derivatives with specific substituent patterns) that are prepared in advance to preemptively overcome resistance mechanisms, allowing the therapy to maintain effectiveness over extended periods by preventing the emergence of resistance rather than responding to it after development
3Reliability
If irreversible EGFR inhibitors are used to target T790M mutations, then activity against resistant mutations is improved, but dose-limiting toxicity increases
Solution Approach 1:
The invention introduces specific local structural modifications to the inhibitor molecule, including particular substituent groups at defined positions (R1-R7), to create localized interactions that specifically recognize and bind to the unique structural features of mutant EGFR, thereby achieving mutation-specific inhibition with improved selectivity and reduced off-target toxicity
Solution Approach 2:
The patent modifies chemical parameters of the inhibitor structure, including the introduction of acrylamide groups and specific substituent patterns, to tune the binding affinity and selectivity, achieving optimal balance between potency against resistant mutations and reduction of dose-limiting toxicity
Data Source
AI summary
Compounds of formula (I)processes for their production and their use as pharmaceuticals.