A Modular Chemistry Platform for the Development of a Cereblon E3 Ligase-Based Partial PROTAC Library

Area of Science:

• Medicinal Chemistry
• Chemical Biology
• Drug Discovery

Background:

• Proteolysis Targeting Chimeras (PROTACs) offer a novel therapeutic strategy for targeted protein degradation.
• Cereblon (CRBN) E3 ligase ligands, like lenalidomide, are crucial components in PROTAC development.
• Previous work demonstrated lenalidomide's C4-phenyl substitution tolerance for PROTACs.

Purpose of the Study:

• To establish a modular chemistry platform for synthesizing diverse lenalidomide-derived CRBN E3 ligase ligands.
• To enable systematic investigation of linker effects in PROTAC development.
• To expand the toolkit for creating PROTACs targeting various proteins.

Main Methods:

• Utilized Suzuki cross-coupling reaction for efficient attachment of substituted phenyl groups to lenalidomide's C4-position.
• Synthesized twelve novel lenalidomide derivatives with varied linker functionalities.
• Explored ortho-, meta-, and para-substituted phenyl modifications.

Main Results:

• Successfully developed a versatile platform for creating modified lenalidomide-based CRBN ligands.
• Demonstrated the feasibility of attaching diverse phenyl substituents and linkers.
• Generated a library of twelve new ligands for PROTAC development.

Conclusions:

• The established platform facilitates the systematic study of linker effects in PROTAC design.
• This approach enhances the development of novel PROTACs for targeted protein degradation therapies.
• The methodology provides a foundation for creating PROTACs against a wider range of protein targets.