Solid Forms of EGFR Kinase Inhibitor Compound 1
Find Innovative SolutionsGenerate Solutions
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 are less effective against the T790M resistance mutation, highlighting a need for mutant-selective EGFR kinase inhibitors that can target specific mutations like L858R and T790M without affecting wild-type EGFR.
Innovation Solution
Development of novel solid forms of 2,4-disubstituted pyrimidine compounds, including Compound 1, which exist in various polymorphs and solvates, offering improved aqueous solubility, stability, and selective inhibition of mutant EGFR kinases, particularly the T790M mutation, while sparing wild-type EGFR.
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 provide therapeutic benefit, but they cause dose-limiting toxicities due to concurrent inhibition of wild-type EGFR and are less effective against T790M resistance mutation
Solution Approach 1:
The patent applies local quality by designing Compound 1 with specific molecular characteristics that enable selective binding to mutant EGFR kinase (T790M and L858R) while avoiding binding to wild-type EGFR. This is achieved through specific structural features including the 2,4-disubstituted pyrimidine core with particular substituent patterns that confer mutation-selectivity, allowing the drug to target only the pathological mutant forms present in cancer cells while sparing normal wild-type EGFR expression in healthy tissues
Solution Approach 2:
The patent employs parameter changes by modifying molecular parameters of the inhibitor compound to achieve selective inhibition. Compound 1 possesses specific physicochemical and structural parameters (molecular weight, hydrophobicity, binding affinity constants) that are optimized to differentiate between mutant and wild-type EGFR. The compound demonstrates altered binding kinetics and affinity profiles that enable preferential interaction with mutant forms, thereby changing the selectivity parameter to resolve the toxicity issue
2Reliability
If current EGFR kinase inhibitors are used, then they inhibit EGFR activity, but they exhibit reduced effectiveness against the T790M resistance mutation
Solution Approach 1:
The patent applies local quality by designing Compound 1 with specific molecular characteristics that enable selective binding to mutant EGFR kinase (T790M and L858R) while avoiding binding to wild-type EGFR. This is achieved through specific structural features including the 2,4-disubstituted pyrimidine core with particular substituent patterns that confer mutation-selectivity, allowing the drug to target only the pathological mutant forms present in cancer cells while sparing normal wild-type EGFR expression in healthy tissues
Solution Approach 2:
The patent applies preliminary action by designing Compound 1 to preemptively address the T790M resistance mechanism. The compound is structurally configured from the outset to accommodate the T790M gatekeeper mutation, which confers resistance to first-generation inhibitors. By incorporating pre-designed structural elements that specifically interact with the threonine 790 methionine substitution, the compound prevents resistance development and maintains effectiveness against mutant forms that would otherwise be inaccessible to conventional inhibitors
Data Source
Figure 1
Figure 2
Figure 3
AI summary
The present invention provides a solid form and compositions thereof, which are as an inhibitor of EGFR kinases and which exhibit desirable characteristics for the same.