Combinatorial Ubiquitination REal-time PROteolysis (CURE-PROs): A Modular Platform for Generating Reversible,...

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Drug Discovery

Background:

• Proteolysis-Targeting Chimeras (PROTACs) are effective protein degraders but face challenges like large size and poor drug-like properties.
• Developing PROTACs requires significant time and effort to optimize linker length and E3 ligase selection for each target.

Purpose of the Study:

• To develop a novel class of small molecule degraders, Combinatorial Ubiquitination REal-time PROteolysis (CURE-PROs), to overcome PROTAC limitations.
• To create a versatile platform for rapid identification of optimal degrader components for various protein targets.

Main Methods:

• Modification of the Coferon platform to generate CURE-PROs using reversible bio-orthogonal linkers (phenylboronic acid and diol/catechol).
• Design of CURE-PROs to self-assemble into covalent heterodimers, bringing target proteins and E3 ligases together.
• Utilizing known ligands for Cereblon, MDM2, VHL, and BRD in the CURE-PRO design.

Main Results:

• Successfully created CURE-PROs that induce degradation of BRD4 both in vitro and in vivo.
• Demonstrated the combinatorial nature of the platform significantly reduces synthesis time and effort.
• Showcased the platform's amenability to screening for new targets and optimizing E3 ligase partners.

Conclusions:

• CURE-PROs represent a promising new strategy for small molecule-based protein degradation, offering advantages over traditional PROTACs.
• The CURE-PRO platform enables efficient and rapid discovery of targeted protein degraders.
• This approach facilitates the optimization of linker properties and E3 ligase selection for diverse therapeutic targets.