Small Molecule Modulators of Human STING Protein
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Solution Overview
Problem
Current therapies for cancer and other diseases lack effective modulation of the human STING protein, as previous compounds like DMXAA and CMA only activate mouse STING, not human STING, leading to failed clinical trials and a need for improved compounds that can modulate the human STING protein.
Innovation Solution
Development of novel compounds of formula (I) that specifically modulate the human STING protein, activating it to treat various diseases by binding to the human STING dimer interface, thereby activating the interferon pathway and immune response.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If compounds like DMXAA and CMA are used to activate STING protein, then immune response is stimulated, but they only activate mouse STING and not human STING, leading to failed clinical trials
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of STING activator compounds to alter their molecular properties. Specifically, the invention identifies and optimizes structural parameters such as the R1 substituent groups (e.g., fluorinated alkyl groups) and the core heterocyclic structure to achieve appropriate binding affinity and selectivity for human STING protein, thereby changing the compound's parameters to overcome species-specific limitations
Solution Approach 2:
The patent applies local quality by focusing on specific local structural features of the compound that determine human STING selectivity. The invention identifies critical local regions such as the R1 substituent positions and specific heterocyclic ring structures that locally interact with human STING binding pockets, making these local structural qualities decisive for achieving human STING activation while maintaining overall compound functionality
2Ease of manufacture
If current therapies are used, then treatment is provided, but effective modulation of human STING protein is not achieved
Solution Approach 1:
The patent applies the intermediary principle by introducing novel small molecule compounds as mediators that specifically bridge the gap between therapeutic intent and human STING activation. These compounds serve as intermediary agents that selectively bind to human STING protein structure, translating the therapeutic goal of STING modulation into actual biological activity, thereby overcoming the ineffectiveness of previous direct approaches
3Measurement precision
If compounds are designed to bind to STING dimer interface, then specific activation is achieved, but compound design and development becomes more complex
Solution Approach 1:
The patent applies the copying principle by using the natural cyclic dinucleotide ligand binding mode as a template or copy for designing synthetic compounds. The invention replicates the key binding features of natural ligands at the STING dimer interface, copying the essential structural elements that enable specific binding while simplifying the overall molecular design through rational based on the natural ligand's binding characteristics
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 activate the human STING protein, inducing a robust immune response, potentially treating cancer, infections, and autoimmune disorders by up-regulating Type-I interferons and cytokines, providing a therapeutic benefit not achieved by previous compounds.
Implementation Method 1
Binding of dsDNA by cyclic GMP-AMP (cGAS) synthase (cGAS) triggers formation of cyclic dinucleotides (CDNs). CDNs are second messenger signalling molecules produced by diverse bacteria and consist of two ribonucleotides that are connected via phosphodiester bonds to make a cyclic structure. CDNs Cyclo-di(GMP), cyclo-di(AMP) and hybrid cyclo-(AMP/GMP) derivatives all bind to STING with subsequent activation of the interferon pathway
Data Source
AI summary
The present invention relates to compounds of formula (I). The compounds maybe used to modulate the Stimulator of Interferon Genes (STING) protein and thereby treat diseases such as cancer and microbial infections.