NLRP3 Modulators Enhance T-Cell Infiltration in Refractory Cancers
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Solution Overview
Problem
Current treatments for cancers with low T-cell infiltration are refractory, meaning they do not respond well to conventional therapies, and there is a need for enhancing innate immune activity to improve treatment outcomes.
Innovation Solution
Development of chemical entities that modulate NLRP3 activity, acting as either full or partial agonists, to increase NLRP3 signaling, which can correct deficiencies in innate immune activity contributing to cancer pathology and progression, thereby enhancing treatment efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional therapies are used for cancers with low T-cell infiltration, then treatment is administered, but treatment response is poor and diseases remain refractory
Solution Approach 1:
The patent changes the immunological parameter by introducing NLRP3 agonists that activate the NLRP3 inflammasome pathway. This activates caspase-1, which processes pro-IL-1β to active IL-1β and pro-IL-18 to active IL-18, thereby changing the immune microenvironment parameters to improve T-cell infiltration and treatment response in previously refractory cancers
Solution Approach 2:
The patent uses NLRP3 agonists as intermediary substances that mediate between the existing immune-deficient state and the desired immune-active state. These compounds act as intermediaries to trigger the inflammasome pathway, which then produces cytokines (IL-1β and IL-18) that restore immune function and enable treatment response
2Adaptability or versatility
If NLRP3 signaling is increased to correct immune deficiency, then innate immune activity is enhanced, but potential off-target effects may occur
Solution Approach 1:
The patent employs partial agonists of NLRP3 that provide sufficient activation to correct immune deficiency but at lower intensities than full agonists. This partial action achieves the therapeutic goal of enhancing innate immune activity while reducing the risk of excessive activation and associated off-target harmful effects
Data Source
AI summary
The present invention provides compounds of Formula (I):wherein all of the variables are as defined herein. These compounds are modulators of NLRP3, which may be used as medicaments for the treatment of proliferative disorders, such as cancer in a subject (e.g., a human).