Indolizine Derivative and Cyclic Dinucleotide Composition for Cancer Therapy
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Solution Overview
Problem
Current immunotherapeutic anticancer agents, such as immune checkpoint inhibitors, have limited efficacy as they only work for certain patients and cancer types, and resistance to treatment can occur. Additionally, systemic administration of type-1 IFN requires high doses, leading to tolerability issues, and STING agonists have shown lower-than-expected disease control rates despite increased pro-inflammatory cytokine production.
Innovation Solution
A composition containing an indolizine derivative compound represented by a specific formula, combined with a cyclic-di-nucleotide, to enhance the activation of the cGAS-STING pathway, thereby increasing immunoreactivity around cancer cells and improving the efficacy of anticancer therapy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If systemic administration of type-1 IFN is used to activate the cGAS-STING pathway, then immunoreactivity around cancer cells increases, but high doses are required leading to tolerability issues
Solution Approach 1:
The patent uses indolizine derivative compounds as intermediary agents that enhance the activity of cyclic-di-nucleotide STING agonists. These intermediaries allow lower doses of the agonist to achieve the same therapeutic effect, thereby reducing tolerability issues while maintaining immunoreactivity activation around cancer cells
Solution Approach 2:
The patent changes the concentration parameter of cyclic-di-nucleotide STING agonists by using them in combination with indolizine derivatives. This parameter change allows achieving therapeutic efficacy at lower concentrations, thus avoiding the tolerability problems associated with high-dose systemic administration
2Productivity
If cyclic-di-nucleotide STING agonists are used to activate the cGAS-STING pathway, then pro-inflammatory cytokine production increases, but disease control rates are lower than expected
Solution Approach 1:
The patent creates a composite therapeutic approach by combining indolizine derivative compounds with cyclic-di-nucleotide STING agonists. This composite strategy enhances the overall therapeutic effect and disease control rate beyond what either agent could achieve alone, despite the agonist's ability to increase cytokine production
3Reliability
If immune checkpoint inhibitors are used for cancer treatment, then efficacy is achieved in some patients, but resistance occurs and efficacy is limited to certain cancer types
Solution Approach 1:
The patent employs a multi-functional combination therapy that targets multiple pathways simultaneously - the indolizine derivatives enhance STING pathway activation while the cyclic-di-nucleotide agonists directly stimulate immune response. This universal approach aims to overcome resistance mechanisms and expand applicability across different cancer types and patient populations
Data Source
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AI summary
The present invention relates to an interferon gene stimulator composition containing an indolizine derivative as an active ingredient. The composition may overcome the problem of low disease control rate, unlike the use of a cyclic-di-nucleotide alone. Specifically, since the composition contains the cyclic-di-nucleotide together with the compound of Formula 1, it may exhibit high activity even when a low concentration of the cyclic-di-nucleotide is used.