Structure-Guided Conformational Restriction Leading to High-Affinity, Selective, and Cell-Active...

Area of Science:

• Medicinal Chemistry
• Drug Discovery
• Biochemistry

Background:

• The protein-protein interaction between Kelch-like ECH-associated protein 1 (Keap1) and nuclear factor erythroid 2-related factor 2 (Nrf2) is a key target for managing oxidative stress-related diseases.
• Developing small molecules to modulate this interaction is a significant therapeutic strategy.

Purpose of the Study:

• To design and synthesize novel noncovalent inhibitors of the Keap1-Nrf2 interaction.
• To enhance binding affinity, cellular activity, and metabolic stability through conformational restriction.

Main Methods:

• Fragment-based drug discovery and structure-guided design using X-ray cocrystal structures.
• Synthesis of fluorenone-based compounds and subsequent optimization via conformational rigidification.
• Biochemical assays to determine binding affinity (Ki) and cellular assays for activity.

Main Results:

• A series of tetrahydroisoquinoline-based inhibitors were developed, showing up to a 223-fold improvement in binding affinity compared to a noncyclic precursor.
• Compound 57 demonstrated potent inhibition with a Ki of 13 nM.
• The optimized compounds exhibited improved metabolic stability and enhanced cellular activity, along with selectivity for the Keap1 Kelch domain.

Conclusions:

• Conformational rigidification, specifically through the tetrahydroisoquinoline scaffold, is an effective strategy for designing potent and drug-like Keap1-Nrf2 inhibitors.
• These findings highlight a promising new class of compounds for therapeutic intervention in oxidative stress-related conditions.