STING PROTAC Compounds for Targeted Degradation in Constitutive Activation
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Solution Overview
Problem
Current treatments for diseases associated with unwanted or uncontrolled activation of STING, such as monogenic autoinflammatory syndromes and autoimmune diseases, rely on high systemic drug exposures, increasing the risk of off-target effects, and are less effective for constitutive activation of STING.
Innovation Solution
Development of proteolysis targeting chimeric (PROTAC) compounds that induce STING degradation by binding to both STING and an E3 ubiquitin ligase, specifically using a STING ligand connected to an Inhibitor of Apoptosis (IAP) E3 ubiquitin ligase ligand via a linker, without forming a covalent bond and exhibiting agonist activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If traditional small molecule inhibitors are used to modulate STING activity, then STING activation can be inhibited, but high systemic drug exposures are required which increase the risk of off-target effects
Solution Approach 1:
The invention extracts the STING protein from the cell and eliminates it through proteolysis. The PROTAC compound binds to STING and an E3 ubiquitin ligase, leading to STING degradation via the proteasome pathway. This removes the target protein entirely rather than merely inhibiting its activity, thereby achieving high specificity without requiring high systemic exposures that cause off-target effects.
Solution Approach 2:
The invention changes the mechanism of action from reversible binding inhibition to irreversible protein degradation. By transforming STING from a stable protein to a degraded protein, the system achieves complete and sustained inhibition of STING activity without the need for continuous high-dose administration, thereby reducing off-target effects.
2Reliability
If traditional inhibitors are used to treat constitutive STING activation, then STING activity can be modulated, but efficacy is reduced compared to activated STING
Solution Approach 1:
The PROTAC mechanism directly removes constitutively active STING protein from the cell through targeted degradation. This is particularly effective for constitutive activation scenarios where traditional inhibitors fail to achieve sufficient efficacy, as the degradation mechanism eliminates the persistent STING protein without requiring continuous drug presence.
Solution Approach 2:
Instead of attempting to block STING activation (the conventional approach), the invention inverts the strategy by directly eliminating STING protein through degradation. This reversal of the approach— from inhibition to elimination—provides superior efficacy against constitutive activation.
3Productivity
If high doses of STING inhibitors are administered to achieve desired efficacy, then STING activation is suppressed, but the risk of off-target effects increases
Solution Approach 1:
The invention achieves complete STING elimination through PROTAC-mediated proteolysis, providing potent and sustained suppression of STING activity. This mechanism achieves high efficacy at lower doses compared to traditional inhibitors, as the degraded STING protein cannot revert to its active state, thereby reducing the dose required and minimizing off-target effects.
4Reliability
If PROTAC compounds are designed with specific E3 ubiquitin ligase ligands, then STING degradation can be achieved, but the selection of appropriate E3 ligases is limited
Solution Approach 1:
The invention applies local quality by selecting CRBN, a highly specific E3 ligase with a well-defined binding pocket, as the degradation machinery. This choice provides precise and controllable STING degradation, as CRBN's specificity ensures that the PROTAC compound acts only on the intended target without affecting other proteins, thereby achieving high reliability despite the limited E3 ligase options.
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 reduce lymphocyte count and inhibit STING activation, providing a therapeutic approach with reduced off-target effects and improved efficacy for conditions driven by constitutive STING activation.
Implementation Method 1
The E3 ligase then recruits an E2 conjugating enzyme to the ternary complex, which ubiquitinates the target protein. This has the effect of labelling the target protein for degradation by the cell's proteasome machinery.
Implementation Method 2
A degrader can then dissociate from the target protein and initiate another cycle of this process in a catalytic manner. Meanwhile, the ubiquitinated target proteins are recognized and degraded by the cell's proteasome machinery.
Data Source
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AI summary
The invention relates to a compound of formula (I): S1-L-E (I), wherein S1 is a STING ligand, L is a Linker, and E is an Inhibitor of Apoptosis (IAP) E3 ubiquitin ligase ligand, wherein the STING ligand does not form a covalent bond with STING and wherein the STING ligand does not exhibit STING agonist activity.