Cyclic Dinucleotide Partial STING Agonists for Lower-Toxicity Cancer Therapy
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Solution Overview
Problem
Existing treatments for conditions associated with impaired STING signaling, such as cancer, lack efficacy and are plagued by toxicity issues, necessitating the development of compounds that modulate STING activity to induce an immune response while minimizing side effects.
Innovation Solution
Development of partial agonists of STING that activate the receptor to induce an immune response and type I interferon production, reducing toxicity by antagonizing full agonists, combined with conventional cancer therapies.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If full agonists of STING are used to induce an immune response, then the immune response is activated, but toxicity increases
Solution Approach 1:
The patent applies partial agonists of STING that provide sufficient immune response activation without the full toxicity of complete agonists. The partial agonists activate the immune response to a controlled extent, achieving therapeutic benefit while reducing harmful effects.
Solution Approach 2:
The patent modifies the agonist activity parameter of STING modulators by developing compounds with partial agonist properties rather than full agonist properties. This parameter change in receptor activation level directly reduces toxicity while maintaining immune response induction.
2Reliability
If existing treatments are used for conditions with impaired STING signaling, then treatment is provided, but efficacy is insufficient and toxicity occurs
Solution Approach 1:
The patent changes the pharmacological parameter of STING activation from full agonism to partial agonism, achieving a balance between efficacy and toxicity. This parameter optimization resolves the contradiction by tuning the activation level to be therapeutically effective without toxic side effects.
Solution Approach 2:
The patent introduces partial agonists as intermediary compounds between no activation and full activation. These intermediaries provide a middle ground that achieves sufficient immune response for treatment efficacy while avoiding the toxicity of full agonists.
3Reliability
If STING activity is increased to treat cancer, then immune response is induced, but side effects increase
Solution Approach 1:
The patent uses partial agonists that provide just enough STING activation to induce anti-tumor immune response without excessive activation that would cause severe side effects. This partial action achieves the minimum effective dose principle.
Solution Approach 2:
The patent optimizes the STING activation parameter to a specific range that is effective for cancer treatment but below the threshold for severe side effects. This parameter control resolves the contradiction between treatment effectiveness and side effect management.
Data Source
AI summary
This disclosure features dinucleotide compounds that modulate Stimulator of Interferon Genes (STING) activity, for use for example in the treatment of cancer. This disclosure also features compositions as well as other methods of using and making the same (Fomula (A)). A and B are each independently selected from the group consisting of Formulae (i), (ii), (iii), and (iv).