Facile Synthesis of Homodimeric Protein Ligands

Area of Science:

• Biochemistry and Chemical Biology
• Medicinal Chemistry
• Drug Discovery

Background:

• Oligomeric proteins (e.g., homodimers, homotrimers) are common biological targets.
• High-affinity ligands for oligomeric proteins can be developed by linking two modest-affinity ligands to form 2:2 complexes.

Purpose of the Study:

• To report a novel, convenient, and efficient "click-like" chemical reaction for protein ligand homodimerization.
• To demonstrate the utility of this reaction in synthesizing homodimeric inhibitors, including proteolysis targeting chimeras (PROTACs).

Main Methods:

• Development of a facile homodimerization reaction for protein ligands.
• The reaction is operationally simple, "click-like", and exhibits broad functional group tolerance.
• Synthesis of homodimeric inhibitors and PROTACs using the developed methodology.

Main Results:

• A new chemical reaction enabling efficient homodimerization of protein ligands was discovered.
• This method simplifies the synthesis of dimeric ligands by requiring only a single precursor.
• Successful synthesis of homodimeric inhibitors and PROTACs was achieved, validating the strategy.

Conclusions:

• The developed "click-like" reaction offers a significant advantage in synthesizing homodimeric protein ligands.
• This approach reduces synthetic complexity and burden, facilitating the creation of dimeric inhibitors and PROTACs.
• The methodology holds promise for advancing drug discovery efforts targeting oligomeric proteins.