A Degron Blocking Strategy Towards Improved CRL4^CRBN Recruiting PROTAC Selectivity

Area of Science:

• Biochemistry
• Pharmacology
• Medicinal Chemistry

Background:

• Small molecules that induce protein degradation are crucial pharmacological tools and emerging clinical agents.
• Achieving selectivity in these molecules is a significant challenge for their full potential.
• CRL4^CRBN-recruiting PROteolysis TArgeting Chimeras (PROTACs) often exhibit intrinsic monovalent degradation via neo-substrate recruitment.

Purpose of the Study:

• To address the selectivity challenge in CRL4^CRBN-recruiting PROTAC design.
• To attenuate or remove the monovalent degradation function of known CRL4^CRBN molecular glues.
• To generate a PROTAC with an improved selectivity profile by applying novel design principles.

Main Methods:

• Leveraged structural insights of CRL4^CRBN neo-substrates.
• Modified known CRL4^CRBN molecular glues (CC-885, Pomalidomide) to block neo-substrate binding.
• Applied design principles to a BRD9 PROTAC (dBRD9-A) to create a selective analogue.
• Utilized computational modeling to assess ternary complex formation.

Main Results:

• Successfully attenuated and removed monovalent degradation functions from CC-885 and Pomalidomide.
• Generated a BRD9 PROTAC analogue with a demonstrably improved selectivity profile.
• Computational modeling confirmed that the degron-blocking design does not impede PROTAC-induced ternary complex formation.

Conclusions:

• The presented design principles offer a strategy to enhance PROTAC selectivity by mitigating off-target degradation.
• The developed tools and methodologies can aid in the design of more selective targeted protein degraders.
• This work contributes to advancing the field of targeted protein degradation for therapeutic applications.