Cyclic Dinucleotides STING Pathway Activation
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Solution Overview
Problem
Current immunotherapy approaches, particularly cytokine administration, are limited by short half-life and require frequent high doses, and there is a need for more effective cancer treatments that can induce therapeutically beneficial cytokines.
Innovation Solution
Development of novel cyclic dinucleotides that activate the STING pathway to induce cytokines, such as those represented by specific compounds of formulae (I) and (II), which can be used in pharmaceutical compositions for cancer treatment.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If cytokines are administered directly for immunotherapy, then immune response is activated, but half-life is short requiring frequent high doses
Solution Approach 1:
The patent uses cyclic dinucleotides (CDNs) as intermediary molecules that activate the STING pathway to induce endogenous cytokine production, rather than administering cytokines directly. This mediator approach extends the duration of action because the CDN-STING mechanism triggers sustained endogenous cytokine production, overcoming the short half-life limitation of direct cytokine administration while maintaining reliable immune response activation
Solution Approach 2:
The invention enables the patient's own immune system to produce the required cytokines through STING pathway activation by CDN agonists. This self-service mechanism eliminates the need for frequent external cytokine administrations, as the body's endogenous production sustains the immune response over extended periods, directly addressing the half-life limitation
2Reliability
If direct cytokine administration is used, then therapeutic effect is achieved, but frequent high doses are required
Solution Approach 1:
Cyclic dinucleotides serve as intermediary agonists that activate the STING pathway, which in turn triggers endogenous cytokine production. This indirect mechanism through CDN-STING-cytokine cascade achieves reliable therapeutic effects while requiring much lower doses and less frequent administration compared to direct cytokine therapy, as the endogenous production sustains therapeutic levels
Solution Approach 2:
The patient's immune system is empowered to self-generate the therapeutic cytokines through STING pathway activation. This self-service approach eliminates the need for frequent high-dose external administrations, as the body's own production mechanisms maintain therapeutic cytokine levels over extended periods, reducing dosing frequency
3Reliability
If STING pathway is activated to induce cytokines, then antitumor efficacy is enhanced, but novel compounds need to be developed
Solution Approach 1:
The patent employs parameter changes by modifying the cyclic dinucleotide structure (creating compounds of formulae I and II with specific substituents R1, R2, X, X1, Z1) to optimize STING pathway activation and antitumor efficacy. These structured modifications systematically enhance therapeutic performance while providing a framework for scalable synthesis of novel compounds
Solution Approach 2:
The invention creates composite cyclic dinucleotide structures combining different substituent groups (R1, R2, X, X1, Z1) to develop optimized STING agonists. This composite approach allows systematic enhancement of antitumor efficacy through structured molecular design while maintaining a manageable development framework for novel compound creation
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
These novel cyclic dinucleotides effectively activate the STING pathway, leading to enhanced antitumor immune efficacy and improved cancer treatment outcomes by inducing cytokines, potentially reducing the frequency and dose of administration.
Implementation Method 1
The binding to STING by an agonist activates a signaling pathway culminating in the induction of Type I IFNs
Implementation Method 2
Activation of STING results in up-regulation of IRF3 and NF-κB pathways leading to induction of Interferon-β and other cytokines
Data Source
AI summary
The present invention is directed to compounds of the formulae I, II and III as shown below (I) (II) (III) wherein all substituents are defined herein, as well as pharmaceutically acceptable compositions comprising compounds of the invention and said compositions for use in the treatment of various disorders.