EGFR Kinase Inhibitor Salt Forms for Mutant Selectivity
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Solution Overview
Problem
Current EGFR kinase inhibitors, such as Tarceva and Iressa, face challenges with dose-limiting toxicities due to concurrent inhibition of wild-type EGFR, and there is a need for mutant-selective inhibitors that effectively target resistant mutations like T790M without affecting wild-type EGFR.
Innovation Solution
Development of novel salt forms of compound 2, including benzenesulfonic acid, camphor sulfonic acid, and hydrobromic acid salts, which selectively inhibit mutant EGFR kinases, particularly the T790M mutation, while sparing wild-type EGFR, thereby improving therapeutic efficacy and reducing toxicities.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current EGFR kinase inhibitors (Tarceva, Iressa) are used to treat non-small cell lung cancer, then they effectively inhibit EGFR activity, but they cause dose-limiting toxicities due to concurrent inhibition of wild-type EGFR
Solution Approach 1:
The patent applies local quality by designing the inhibitor to have different binding affinities for different EGFR states. The compound selectively binds to and inhibits mutant EGFR (with activated kinase activity) while having reduced affinity for wild-type EGFR (with basal kinase activity). This differential binding is achieved through specific molecular interactions that exploit the conformational differences between mutant and wild-type EGFR, allowing selective inhibition at the molecular level.
Solution Approach 2:
The patent employs parameter changes by modifying the chemical structure of EGFR inhibitors to alter their binding characteristics. Specifically, the compounds are designed with structural features that change their affinity parameters for different EGFR variants. The molecular structure is optimized to achieve a specific binding affinity ratio between mutant and wild-type EGFR, enabling selective inhibition based on kinetic and thermodynamic parameter differences.
2Reliability
If second-generation covalent inhibitors (BIBW2992, HKI-272, PF-0299804) are used to target T790M resistance mutation, then they are effective against the mutation, but they exhibit dose-limiting toxicities due to concurrent inhibition of wild-type EGFR
Solution Approach 1:
The patent applies local quality by designing the inhibitor to have different binding affinities for different EGFR states. The compound selectively binds to and inhibits mutant EGFR (with activated kinase activity) while having reduced affinity for wild-type EGFR (with basal kinase activity). This differential binding is achieved through specific molecular interactions that exploit the conformational differences between mutant and wild-type EGFR, allowing selective inhibition at the molecular level.
Solution Approach 2:
The patent employs parameter changes by modifying the chemical structure of EGFR inhibitors to alter their binding characteristics. Specifically, the compounds are designed with structural features that change their affinity parameters for different EGFR variants. The molecular structure is optimized to achieve a specific binding affinity ratio between mutant and wild-type EGFR, enabling selective inhibition based on kinetic and thermodynamic parameter differences.
Data Source
AI summary
The present invention provides a salt form and compositions thereof, which are useful as an inhibitor of EGFR kinases and which exhibits desirable characteristics for the same.