Development of versatile solid-phase methods for syntheses of PROTACs with diverse E3 ligands

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Drug Discovery

Background:

• Developing potent proteolysis-targeting chimeras (PROTACs) necessitates exploring diverse ubiquitin ligase (E3 ligase) ligands and linker chemistries.
• Previous solid-phase synthesis of PROTACs primarily utilized cereblon (CRBN) ligands.

Purpose of the Study:

• To establish a versatile solid-phase synthesis platform for PROTACs with expanded E3 ligase ligand options.
• To investigate the impact of different E3 ligase ligands (VHL, IAP) and linker types (PEG vs. alkyl) on PROTAC activity.

Main Methods:

• Developed a facile and rapid solid-phase synthesis method for PROTACs.
• Incorporated Von Hippel-Lindau (VHL) and inhibitor of apoptosis protein (IAP) E3 ligase ligands alongside cereblon (CRBN) ligands.
• Synthesized PROTACs targeting bromodomain-containing protein 4 (BRD4) using polyethylene glycol (PEG) linkers.

Main Results:

• Demonstrated the successful solid-phase synthesis of PROTACs using VHL and IAP ligands.
• Western blotting revealed that E3 ligase type and linker composition significantly influence PROTAC efficacy.
• The developed method allows for rapid generation of PROTAC libraries with diverse ligand and linker combinations.

Conclusions:

• The novel solid-phase synthesis platform enhances PROTAC design diversity by enabling the use of various E3 ligases and linkers.
• This approach facilitates the efficient exploration of structure-activity relationships for PROTAC development.
• The method supports the rapid synthesis of customized PROTACs for targeted protein degradation.