Efficient Targeted Degradation via Reversible and Irreversible Covalent PROTACs

Area of Science:

• Chemical Biology
• Drug Discovery
• Molecular Degradation Technologies

Background:

• Proteolysis targeting chimeras (PROTACs) enable targeted protein degradation but are limited by the need for potent binders.
• Covalent PROTACs offer enhanced potency but can negate the catalytic nature of PROTACs.
• Reversible covalent PROTACs aim to combine the benefits of covalent binding with catalytic regeneration.

Purpose of the Study:

• To investigate the efficacy of reversible covalent PROTACs for targeted protein degradation.
• To compare the performance of reversible covalent PROTACs against noncovalent and irreversible covalent PROTACs.
• To evaluate PROTACs in a clinically relevant model system, Bruton's tyrosine kinase (BTK).

Main Methods:

• Design and synthesis of noncovalent, irreversible covalent, and reversible covalent PROTACs targeting BTK.
• Assessment of protein degradation efficiency (DC50) and percentage degradation.
• Evaluation of B cell activation inhibition and BTK degradation in patient-derived chronic lymphocytic leukemia cells.

Main Results:

• All tested PROTACs achieved efficient BTK degradation (<10 nM DC50, >85% degradation).
• Reversible covalent PROTACs demonstrated potent degradation, with one compound showing enhanced selectivity.
• PROTACs exhibited superior inhibition of B cell activation and potent BTK degradation in primary leukemia cells compared to ibrutinib.

Conclusions:

• Reversible covalent PROTACs are effective for targeted protein degradation, offering advantages over existing modalities.
• The developed PROTACs show promise for treating B cell malignancies like chronic lymphocytic leukemia.
• These findings support the development of covalent PROTACs for challenging therapeutic targets.