NLRP3 Partial Agonists for Cancer Therapy
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Solution Overview
Problem
Current treatments for conditions associated with repressed or impaired NLRP3 signaling, such as cancer, lack effective modulators that can agonize NLRP3 to enhance its activity without causing full activation, which is necessary for therapeutic benefits.
Innovation Solution
Development of chemical entities, including compounds and their pharmaceutically acceptable salts, hydrates, or cocrystals, that act as partial or full agonists of NLRP3, capable of binding to NLRP3 to increase its activity, stabilize its conformation, or alter its distribution, thereby modulating its activity for therapeutic use in treating diseases like cancer.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If full agonists of NLRP3 are used to activate the receptor, then therapeutic benefits are achieved, but adverse effects from full activation occur
Solution Approach 1:
The patent applies partial agonism by designing compounds that activate NLRP3 to a controlled extent rather than full activation. This allows the therapeutic benefits of NLRP3 activation to be achieved while avoiding the adverse effects associated with complete activation, directly resolving the contradiction between efficacy and safety
2Reliability
If NLRP3 activity is enhanced to treat conditions with repressed signaling, then therapeutic benefits are achieved, but the risk of overactivation increases
Solution Approach 1:
The patent changes the activation parameter of NLRP3 from binary (on/off) to a continuous scale by using partial agonists with varying efficacies. This allows precise control over the degree of activation, enabling treatment of repressed signaling conditions while maintaining activation levels below the overactivation threshold
Data Source
AI summary
This disclosure features compounds of Formula I, or a pharmaceutically acceptable salt thereof:in which R1, R2, R3, and R4 are as defined herein. These compounds are modulators of NLRP3, which are useful, e.g., for treating a condition, disease or disorder in which a decrease in NLRP3 activity (e.g., a condition, disease or disorder associated with repressed or impaired NLRP3 signaling) contributes to the pathology and/or symptoms and/or progression of the condition, disease or disorder (e.g., cancer) in a subject (e.g., a human). This disclosure also features compositions as well as other methods of using and making the same.