Affinity and cooperativity modulate ternary complex formation to drive targeted protein degradation

Area of Science:

• Biochemistry
• Molecular Biology
• Drug Discovery

Background:

• Targeted protein degradation using proteolysis targeting chimeras (PROTACs) is a promising therapeutic strategy.
• Designing effective PROTACs is complex due to multiple degradation steps, hindering structure-activity relationship establishment.

Purpose of the Study:

• To characterize PROTAC-mediated ternary complex formation and degradation for SMARCA2 and BRD4 using VHL-recruiting PROTACs.
• To evaluate how PROTAC architecture variations impact ternary complex attributes and degradation activity.
• To establish a predictive framework for designing potent PROTAC degraders.

Main Methods:

• Utilized VHL-recruiting PROTACs targeting SMARCA2 and BRD4.
• Varied PROTAC components to assess ternary complex formation and degradation parameters.
• Developed a ternary-complex structure modeling workflow to calculate interface buried surface area.

Main Results:

• Ternary complex binding affinity and cooperativity were found to correlate well with degradation potency and initial degradation rates.
• The developed ternary-complex structure modeling workflow accurately predicted binding affinity based on calculated buried surface area.
• Specific PROTAC architecture modifications influenced both ternary complex formation and degradation efficiency.

Conclusions:

• PROTAC binding affinity and cooperativity are key determinants of degradation potency.
• A predictive framework based on ternary complex modeling can guide the rational design of more effective PROTACs.
• This study provides insights into optimizing PROTAC design for targeted protein degradation therapies.