Macrocyclic Compounds from Ansamycin Antibiotic Class as Inhibitors of PD1-PDL1 Protein-Protein Interaction

Area of Science:

• Immunology
• Oncology
• Medicinal Chemistry

Background:

• Tumor cells evade immune surveillance through the interaction between programmed cell death protein 1 (PD1) on T cells and programmed cell death ligand 1 (PDL1) on cancer cells.
• Inhibiting the PD1-PDL1 interaction is a validated therapeutic strategy, with several antibodies approved for cancer treatment.
• Developing small-molecule inhibitors for the PD1-PDL1 target is challenging due to the large, complex binding interface.

Purpose of the Study:

• To explore macrocyclic compounds as potential small-molecule inhibitors of the PD1-PDL1 interaction.
• To identify novel chemical scaffolds capable of disrupting this critical immune checkpoint pathway.

Main Methods:

• Screening of macrocyclic compounds, specifically from the ansamycin antibiotic class, for PD1-PDL1 inhibitory activity.
• Characterization of inhibitory potency using IC50 values.

Main Results:

• Several macrocyclic compounds, derived from ansamycin antibiotics, demonstrated inhibition of the PD1-PDL1 interaction.
• Rifabutin, a macrocyclic antibiotic, exhibited a notable IC50 of approximately 25 µM against the PD1-PDL1 interaction.
• This inhibition was achieved by a relatively low molecular weight compound, highlighting the potential of macrocycles.

Conclusions:

• Macrocyclic compounds, particularly ansamycin antibiotics like Rifabutin, represent a promising new class of small-molecule inhibitors for the PD1-PDL1 pathway.
• These findings provide a foundation for developing more potent and selective small-molecule drugs targeting this key cancer immunotherapy target.
• Macrocycles offer a viable alternative scaffold for overcoming the challenges in targeting large protein-protein interactions like PD1-PDL1.