Small-Molecule Degraders beyond PROTACs-Challenges and Opportunities

Area of Science:

• Biochemistry
• Molecular Biology
• Drug Discovery

Background:

• Targeted protein degradation (TPD) utilizes cellular machinery to deplete specific proteins, shifting drug discovery from occupancy-driven to event-driven mechanisms.
• Proteolysis-targeting chimeras (PROTACs) are heterobifunctional molecules that induce protein degradation but often possess unfavorable physicochemical properties due to their large size.

Purpose of the Study:

• To identify small molecules that induce targeted protein degradation, offering a simpler alternative to PROTACs with potentially improved properties.
• To explore alternative small-molecule degraders that overcome the limitations of traditional modulators and PROTACs.

Main Methods:

• Conducted a high-throughput screen of 111,000 compounds using a cellular HiBiT assay to identify novel small-molecule degraders.
• Employed methods for triage, characterization, selectivity assessment, and mode of action determination for identified compounds.

Main Results:

• Successfully identified alternative small-molecule degraders through the high-throughput screening approach.
• Preliminary analysis indicates the identification of compounds that induce targeted protein degradation.

Conclusions:

• Small-molecule degraders represent an exciting and potentially advantageous approach for targeted protein degradation (TPD) in drug discovery.
• A general screening approach is effective in identifying starting points for developing small-molecule degraders with potentially favorable physicochemical properties compared to PROTACs.