Alkynyl Quinazoline Inhibitors for Oncogenic ErbB Variants
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Solution Overview
Problem
Existing ErbB inhibitors do not satisfactorily address the variable responsiveness of cancer patients with oncogenic mutations, particularly in tumors expressing oncogenic variants like EGFR-Viii, EGFR-Vii, and HER2-S310F, leading to paradoxical activation and treatment resistance.
Innovation Solution
Development of non-Type I small molecule inhibitors, such as neratinib, that target oncogenic variants of ErbB receptors, including EGFR-Viii, EGFR-Vii, and HER2-S310F, by inhibiting covalently activated forms and preventing paradoxical activation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If Type I inhibitors are used to treat cancers with oncogenic variants, then initial therapeutic response may be observed, but paradoxical activation occurs leading to treatment resistance
Solution Approach 1:
The patent transitions from Type I inhibitors (which bind to active conformation) to Type II inhibitors (which bind to inactive conformation), fundamentally changing the binding parameter and mechanism to eliminate paradoxical activation while maintaining therapeutic efficacy against oncogenic variants
Solution Approach 2:
Instead of inhibiting the active form of the receptor (Type I approach), the patent employs Type II inhibitors that target the inactive conformation, inverting the traditional inhibition strategy to achieve more consistent therapeutic responses without paradoxical activation
2Adaptability or versatility
If existing ErbB inhibitors are used, then some cancer types may be treated, but variable responsiveness is observed across different patients with oncogenic mutations
Solution Approach 1:
The patent develops Type II inhibitors with broad spectrum activity against multiple oncogenic variants including EGFR exon 20 insertions, EGFR-VIII, and HER2 mutations, creating a universal inhibitor class that addresses variable responsiveness across different cancer types and genetic backgrounds
3Duration of action of moving object
If Type I inhibitors are administered, then initial inhibition of oncogenic variants occurs, but resistance develops due to paradoxical activation
Solution Approach 1:
The patent changes the inhibition mechanism from Type I (active conformation binding) to Type II (inactive conformation binding), which prevents the development of resistance through paradoxical activation and sustains therapeutic efficacy over longer treatment durations
Data Source
AI summary
The present disclosure relates to compounds of Formula (I′):and pharmaceutically acceptable salts and stereoisomers thereof. The present disclosure also relates to methods of preparation these compounds, compositions comprising these compounds, and methods of using them in the prevention or treatment of abnormal cell growth in mammals, especially humans.