Dual-Function STING Compounds for Systemic Immune Activation
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Solution Overview
Problem
Existing STING agonists for cancer treatment have limited systemic activity due to poor stability, necessitating local delivery and restricting their utility.
Innovation Solution
Development of dual-functioning compounds comprising a STING agonist moiety and a second active moiety, such as a PI3K or IDO inhibitor, to enhance immune response activation through the cGAS-STING pathway.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If first generation STING agonists are used for cancer treatment, then safety is improved, but systemic activity is limited due to poor stability
Solution Approach 1:
The patent combines a STING agonist moiety with a second active moiety (such as a PI3K inhibitor or IDO inhibitor) into a single dual-functioning compound. This merging allows the compound to simultaneously activate the cGAS-STING pathway and modulate immune response through the second moiety, thereby improving systemic activity and stability while maintaining the safety profile of first-generation STING agonists.
Solution Approach 2:
The dual-functioning compound represents a composite molecular structure where a STING agonist component is chemically linked to a second pharmacologically active component. This composite structure enables the compound to exhibit multiple therapeutic effects: STING pathway activation for immune stimulation and additional immune modulation through the second moiety, overcoming the limitations of poor stability and limited systemic activity.
2Stability of the object's composition
If local delivery is used for STING agonists, then stability is maintained, but utility is restricted
Solution Approach 1:
The dual-functioning compound is designed to perform multiple functions within a single molecule: it acts as a STING agonist to activate immune response and simultaneously incorporates a second active moiety (PI3K or IDO inhibitor) to modulate immune signaling. This multi-functionality allows the compound to be effective through various delivery routes (systemic, local, intravenous, etc.), thereby expanding utility while maintaining stability.
3Reliability
If dual-functioning compounds are developed, then immune response activation is enhanced, but molecular complexity increases
Solution Approach 1:
The patent merges two pharmacologically active components into a single molecular entity through chemical linkage. The STING agonist moiety is covalently bonded to a second active moiety (such as a PI3K inhibitor or IDO inhibitor) via a linker group, creating a dual-functioning compound that enhances immune response activation through coordinated action of both moieties while managing molecular complexity through rational molecular design.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The compounds effectively stimulate Type I IFN and inflammatory cytokine production, offering improved systemic immune activation and potential therapeutic benefits for cancer, autoimmune, and inflammatory diseases.
Implementation Method 1
The innate immune agonist STING (Stimulator of Interferon Genes) binds its natural ligand 2′3′-cGAMP (cyclic guanosine-adenosine monophosphate) and then, by way of its signaling pathway, induces the expression of interferons, inflammatory factors, and autophagy genes. Microbial infection, tumor DNA, and self-damaging DNA are three factors that induce the activation of the cGAS-STING signaling pathway
Data Source
AI summary
The present disclosure provides dual functioning compounds, compositions, formulations, and methods for inducing or modulating an immune or inflammatory response and treating diseases or disorders (e.g., cancer, autoimmune diseases, inflammatory diseases, and infectious diseases) with the compounds or compositions thereof. In particular disclosed herein are dual functioning compounds comprising a stimulator of interferon (IFN) genes (STING) agonist moiety and a second active moiety selected from an indoleamine 2,3-dioxygenase (IDO) inhibitor and phosphatidylinositol 3-kinase (PI3K) inhibitor, and compositions and formulations thereof.