Optimization Efforts for Identification of Novel Highly Potent Keap1-Nrf2 Protein-Protein Interaction Inhibitors

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Biochemistry

Background:

• Optimizing protein-protein interaction (PPI) inhibitors for high activity and favorable properties is challenging.
• A previously discovered Keap1-Nrf2 PPI inhibitor (compound 8) showed moderate in vivo activity.
• Further optimization of PPI inhibitors is crucial for therapeutic development.

Purpose of the Study:

• To optimize a novel Keap1-Nrf2 PPI inhibitor for enhanced potency and pharmacokinetic properties.
• To explore structure-activity relationships by targeting specific hot spots and water molecules.
• To identify promising chemical probes for further research in Keap1-Nrf2 pathway modulation.

Main Methods:

• Structure-based drug design targeting high energy water molecules and Ser602.
• Ligand efficiency (LE)-guided exploration of chemical space.
• Evaluation of pharmacokinetic (PK) profiles, including solubility, metabolic stability, and membrane permeability.
• In vivo efficacy studies in a rat model.

Main Results:

• Identified two novel Keap1-Nrf2 PPI inhibitors, compounds 22 and 33.
• Achieved improved aqueous solubility, metabolic stability, and membrane permeability.
• Demonstrated more potent in vivo activities compared to the parent compound.
• Compound 22 and 33 exhibited favorable pharmacokinetic profiles.

Conclusions:

• The optimized inhibitors (22 and 33) represent significant advancements over the initial compound.
• Targeting specific hot spots and employing LE-guided optimization are effective strategies for PPI inhibitor development.
• Compounds 22 and 33 are promising chemical probes for studying the Keap1-Nrf2 pathway.