Development of PRC1 Inhibitors Employing Fragment-Based Approach and NMR-Guided Optimization.

Area of Science:

• Biochemistry
• Molecular Biology
• Medicinal Chemistry

Background:

• Polycomb Repressive Complex 1 (PRC1) is crucial for transcriptional silencing.
• PRC1 dysregulation is implicated in various cancers, making it a therapeutic target.
• Targeting PRC1 offers potential for novel cancer treatments.

Purpose of the Study:

• To optimize initial weak PRC1 inhibitors into potent therapeutic agents.
• To explore the structure-activity relationship (SAR) of PRC1 inhibitors.
• To develop novel inhibitors targeting both canonical and noncanonical PRC1 complexes.

Main Methods:

• NMR-based fragment screening to identify initial ligands.
• Structure-activity relationship (SAR) studies guided by NMR and biochemical assays.
• Medicinal chemistry optimization of lead compounds.

Main Results:

• Identified and optimized the weak ligand RB-1 into potent PRC1 inhibitors RB-3 and RB-4.
• RB-4 demonstrates binding to both RING1A and RING1B proteins.
• RB-4 inhibits the activity of RING1B-BMI1 and RING1B-PCGF1, targeting both canonical and noncanonical PRC1 complexes.

Conclusions:

• Successful optimization of PRC1 inhibitors through integrated NMR and medicinal chemistry approaches.
• RB-4 represents a potent inhibitor effective against both canonical and noncanonical PRC1 complexes.
• Developed compounds hold promise for exploring PRC1 inhibition as a cancer therapy.