Macrocyclic Compounds from Ansamycin Antibiotic Class as Inhibitors of PD1-PDL1 Protein-Protein Interaction
Sachin P Patil1, Suk-Chung Yoon2, Abhay G Aradhya2
1NanoBio Laboratory, Department of Chemical Engineering, Widener University.
Abstract:
The ability of tumors to escape from immune destruction is attributed to the protein-protein interaction between programmed cell death protein 1 (PD1) and programmed cell death ligand 1 (PDL1) proteins expressed by immune T cells and cancer cells, respectively. Therefore, pharmacological inhibition of the PD1-PDL1 interaction presents an important therapeutic target against a variety of tumors expressing PDL1 on their cell surface. Recently, five antibodies have been approved and several are in clinical trials against the PD1-PDL1 protein-protein interaction target. In contrast, there are very few reports of small-molecule inhibitors of PD1-PDL1 interaction, and most of them have relatively modest or weak inhibition activities, emphasizing the difficulty in designing small-molecule inhibitors against this challenging target. Therefore, we focused our attention on macrocycles that are known to exhibit target activity comparable to large macromolecules despite having molecular weights closer to small, drug-like molecules. In this context, our present study led to the identification of several macrocyclic compounds from the ansamycin antibiotics class to be inhibitors of PD1-PDL1 interaction. Importantly, one of these macrocyclic antibiotics, Rifabutin, showed an IC50 value of ca. 25 µM. This is remarkable considering it has a relatively low molecular weight and still is capable of inhibiting PD1-PDL1 protein-protein interaction whose binding interface spans over ca. 1970 Å2. Thus, these macrocycles may serve as guiding points for discovery and optimization of more potent, selective small-molecule inhibitors of PD1-PDL1 interaction, one of the most promising therapeutic targets against cancer.
Insights
Tumors evade immune destruction via the programmed cell death protein 1 (PD1) and programmed cell death ligand 1 (PDL1) interaction. This study identifies macrocyclic ansamycin antibiotics, like Rifabutin, as novel inhibitors of this crucial cancer target.
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.
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