Phenyl Dihydrouracil: An Alternative Cereblon Binder for PROTAC Design

Area of Science:

• Medicinal Chemistry
• Chemical Biology
• Drug Discovery

Background:

• Thalidomide analogues are crucial in Proteolysis Targeting Chimera (PROTAC) development but suffer from inherent chemical instability, particularly hydrolysis in cell culture media.
• Phenyl glutarimide (PG)-based PROTACs demonstrated improved stability and protein degradation compared to traditional analogues.
• Optimization efforts focused on enhancing stability and removing chiral centers present in PG-based PROTACs.

Purpose of the Study:

• To design and synthesize novel phenyl dihydrouracil (PD)-based PROTACs.
• To evaluate and compare the physicochemical and pharmacological properties of PD-PROTACs against IMiD and PG analogues.
• To assess the potential of PD-PROTACs as a more stable and effective alternative in targeted protein degradation.

Main Methods:

• Design and synthesis of LCK-directing PD-PROTACs.
• Comparative analysis of chemical stability under physiological conditions.
• Evaluation of protein degradation efficacy and cellular potency in vitro.
• Assessment of physicochemical properties including solubility and stability.

Main Results:

• PD-PROTACs exhibited superior chemical stability compared to IMiD and PG analogues.
• The developed PD-PROTACs demonstrated efficient LCK protein degradation.
• Elimination of the chiral center in PD-based PROTACs resolved racemization issues and improved overall performance.
• PD-PROTACs showed enhanced cellular potency and improved pharmacokinetic profiles.

Conclusions:

• Phenyl dihydrouracil (PD)-based PROTACs represent a significant advancement in PROTAC technology, offering enhanced chemical stability and protein degradation efficiency.
• PD-PROTACs provide a promising platform for developing next-generation therapeutics with improved drug-like properties.
• The design strategy overcomes key limitations of existing thalidomide-based PROTACs, paving the way for more robust targeted protein degraders.