Alternative Binding-Mode BTK Inhibitors for C481 Mutations
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Solution Overview
Problem
Current BTK inhibitors face challenges in effectively targeting Bruton's tyrosine kinase and are susceptible to drug resistance due to mutations, such as C481S, C481Y, C481R, and C481F, limiting their efficacy in treating diseases involving B cells or mast cells.
Innovation Solution
Development of BTK inhibitor compounds with a different binding mode, specifically targeting cysteine residue C481, which are effective against both wild-type BTK and mutated forms, including C481 mutations.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current BTK inhibitors are used to target Bruton's tyrosine kinase, then BTK inhibition activity is achieved, but drug resistance develops due to mutations such as C481S, C481Y, C481R, and C481F
Solution Approach 1:
The patent changes the binding parameters and mode of the BTK inhibitor by designing compounds that bind to a different site or conformation on the BTK enzyme, specifically targeting the ATP-binding pocket in a unique manner that prevents mutation-based resistance while maintaining inhibition efficacy
Solution Approach 2:
Instead of designing inhibitors that bind to the conventional active site of BTK, the patent inverts the approach by developing compounds with a different binding mode that targets an alternative region or mechanism of BTK function, thereby achieving inhibition through a non-traditional pathway that is not susceptible to common mutations
Data Source
AI summary
Bruton's tyrosine kinase (BTK) inhibitors have the following Formula (I) or (II):