NF-kB Inhibitor Compounds Blocking p65 RelB c-Rel DNA Binding
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Solution Overview
Problem
Current treatments for diseases associated with NF-κB activation, such as cancer, inflammation, and autoimmune diseases, are limited in efficacy and often come with adverse effects, as they primarily target the canonical NF-κB pathway without effectively inhibiting the non-canonical and hybrid pathways.
Innovation Solution
Development of compounds that inhibit the binding of NF-κB components, such as p65, RelB, and c-Rel to DNA, blocking both the canonical and non-canonical pathways, thereby modulating gene expression and signal transduction through the NF-κB pathway.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current treatments targeting only the canonical NF-κB pathway are used, then the treatment mechanism is simple, but the treatment efficacy is limited and cannot effectively inhibit non-canonical and hybrid pathways
Solution Approach 1:
The compound is designed to simultaneously inhibit multiple NF-κB pathways (canonical, non-canonical, and hybrid) through a single molecular structure. This multi-functional inhibitor blocks both canonical pathway components (IκBα, IκBβ, IκBε, p65) and non-canonical pathway components (RelB, c-Rel, p52), achieving broad-spectrum NF-κB inhibition with one agent rather than requiring multiple pathway-specific treatments
2Object-affected harmful factors
If existing NF-κB inhibitors like DHMEQ are used, then they show some therapeutic effect, but they exhibit cytotoxicity and reduced potency compared to the new compounds
Solution Approach 1:
The compound optimizes key pharmacological parameters including increasing binding affinity for NF-κB components (p65, RelB, c-Rel) through structural modifications, adjusting molecular properties to enhance selectivity and reduce off-target effects, and tuning the compound's chemical characteristics to improve pharmacokinetic profile and reduce cytotoxicity while maintaining or enhancing inhibitory potency
Data Source
Figure 1A~1B
Figure 2
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AI summary
The invention relates to compounds of formulae (1) and (2), and pharmaceutically acceptable salts thereof for the treatment of cancer, inflammation, auto-immune diseases, diabetes and diabetic complications, infection, cardiovascular disease and ischemia-reperfusion injuries.