Design and Evaluation of PROTACs Targeting Acyl Protein Thioesterase 1

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Computational Biology

Background:

• PROTAC linker design is largely empirical.
• Acyl protein thioesterase 1 (APT1) is a target for therapeutic intervention.
• Developing efficient and selective PROTACs requires optimized linker strategies.

Purpose of the Study:

• To utilize computational software for rational PROTAC linker design.
• To investigate the efficacy and selectivity of sulfonyl-fluoride-based PROTACs targeting APT1.
• To evaluate the utility of PRosettaC in predicting PROTAC performance.

Main Methods:

• Employed PRosettaC computational software for PROTAC design.
• Generated ternary complex models to guide linker selection.
• Synthesized sulfonyl-fluoride-based PROTACs with suggested alkyl linkers.
• Assessed APT1 degradation using Western blotting.
• Determined PROTAC selectivity via activity-based protein profiling.

Main Results:

• PRosettaC efficiently generated ternary complex models.
• Alkyl linkers were identified as preferred for targeting APT1.
• Synthesized PROTACs demonstrated efficient APT1 degradation.
• An alkyl linker-based PROTAC exhibited high selectivity among serine hydrolases.

Conclusions:

• PRosettaC can effectively guide PROTAC linker design.
• Combining computational methods with chemoproteomics aids PROTAC development.
• This approach facilitates early-stage assessment of PROTAC potency and selectivity.