Pyrimidine Compounds Targeting EGFR Kinase Mutations
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Solution Overview
Problem
Current tyrosine kinase inhibitors (TKIs) for EGFR mutations, such as C797S, T790M, and L858R, face challenges in maintaining efficacy due to resistance and altered binding properties, necessitating the development of compounds that target the ATP binding pocket in the kinase domain for enhanced activity against EGFR and HER2 mutations.
Innovation Solution
The development of pyrimidine compounds, specifically represented by formulas (I) and (II), which act as EGFR kinase inhibitors by targeting a cavity near the ATP binding pocket, demonstrating activity against C797S, L858R, T790M, and other sensitive mutations, including potent inhibition of HER2.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current TKIs are used to treat EGFR mutations, then clinical activity is achieved, but resistance develops due to mutations like C797S that abolish covalent binding
Solution Approach 1:
The patent modifies the chemical structure of TKIs by changing the quinazoline core to a pyrimidine structure with specific substituent patterns (formula I and II). This structural parameter change allows the compound to maintain binding affinity to EGFR kinase domain while avoiding resistance mechanisms that affect conventional TKIs, particularly the C797S mutation that abolishes covalent binding of osimertinib
Solution Approach 2:
The invention introduces specific local modifications to the TKI molecule, including particular substituent groups at defined positions on the pyrimidine ring (R1-R16 substituents with specific chemical properties). These local quality changes enable selective interaction with the ATP binding pocket and adjacent cavities in the kinase domain, providing enhanced specificity and resistance to mutation-induced binding loss
2Reliability
If TKIs target the ATP binding pocket, then EGFR kinase activity is inhibited, but binding properties are altered reducing efficacy against certain mutations
Solution Approach 1:
The pyrimidine compounds of formula I and II are designed to perform multiple functions: they inhibit wild-type EGFR, T790M mutant, and C797S mutant, as well as demonstrating potent HER2 inhibition. The molecular structure incorporates features that enable broad-spectrum kinase inhibition while maintaining selectivity, making a single compound effective against multiple mutation types and related kinase targets
Data Source
AI summary
The present disclosure provides pyrimidine compounds useful as tyrosine kinase inhibitors, and particularly epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) inhibitors. The disclosed EGFR inhibitors are effective against acquired resistance mutations appearing after treatment of existing EGFR inhibitors. The present disclosure also provides methods of treating cancer using pyrimidine compounds and pharmaceutical compositions comprising pyrimidine compounds. The methods of treating cancer may be directed to cancer with acquired resistance mutations.