STING PROTAC Degraders for Sustained Inhibition With Lower Off-Target Risk
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing STING inhibitors require high systemic drug exposures to maintain inhibition, leading to a risk of unwanted off-target effects and are less effective against constitutive activation of STING, which is associated with various diseases.
Innovation Solution
Development of proteolysis targeting chimeric (PROTAC) compounds that induce STING degradation by binding to both STING and an E3 ubiquitin ligase, without forming covalent bonds and exhibiting agonist activity, using a STING ligand connected to an E3 ubiquitin ligase ligand via a linker.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If traditional STING inhibitors are used to maintain inhibition, then STING activity is suppressed, but high systemic drug exposures are required leading to unwanted off-target effects
Solution Approach 1:
The inhibitor molecule is divided into two distinct functional modules: a STING-binding module (containing a STING ligand) and a protein degradation module (PROTAC component with E3 ligase binding domain). These modules are connected via a linker, allowing the molecule to simultaneously bind STING and recruit the proteasome degradation machinery, thereby achieving reliable STING suppression through degradation rather than reversible inhibition
Solution Approach 2:
The invention changes the mechanism of action from reversible inhibition to irreversible degradation. By designing the inhibitor as a PROTAC that recruits the ubiquitin-proteasome system, the STING protein is permanently degraded rather than temporarily inhibited, maintaining suppression efficacy without requiring continuous high drug exposure, thus reducing off-target effects
2Reliability
If traditional STING inhibitors are used, then STING activity is inhibited, but the approach is less effective against constitutive activation of STING
Solution Approach 1:
The PROTAC inhibitor is designed to bind to constitutively activated STING and recruit the E3 ubiquitin ligase complex, initiating protein degradation before the constitutive activation can cause harm. The molecule contains a STING ligand module that recognizes and binds to STING regardless of its activation state, followed by a PROTAC module that triggers degradation, effectively neutralizing constitutive activation
Solution Approach 2:
The invention transitions from reversible inhibition to irreversible degradation, which is particularly effective against constitutive activation. By degrading the STING protein rather than merely inhibiting its activity, the PROTAC approach eliminates the source of constitutive activation, providing reliable efficacy where traditional inhibitors fail
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 achieve effective STING degradation with reduced off-target effects, providing therapeutic benefits in diseases driven by unwanted or uncontrolled STING activation.
Implementation Method 1
the degrader binds to both the target protein and E3 ubiquitin ligase simultaneously to form a ternary complex
Implementation Method 2
The E3 ligase then recruits an E2 conjugating enzyme to the ternary complex, which ubiquitinates the target protein
Implementation Method 3
The ubiquitinated target proteins are recognized and degraded by the cell's proteasome machinery
Data Source
Figure 1
Figure 2A~2C
Figure 3
AI summary
The invention relates to agents capable of degrading STING, composition comprising said agents and medical uses thereof.