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An Oncogenic Hepatocyte-Induced Orthotopic Mouse Model of Hepatocellular Cancer Arising in the Setting of Hepatic Inflammation and Fibrosis
Published on: September 12, 2019
Virtual Screening and Biological Evaluation of Potential PD-1/PD-L1 Immune Checkpoint Inhibitors as
Monica A Kamal1, Hedy A Badary2, Dalia Omran2
1Molecular Pharmacology Research Group, Department of Pharmacology and Toxicology, Faculty of Pharmacy and Biotechnology, German University in Cairo, 11835 Cairo, Egypt.
Abstract:
Blockade of the programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) immune checkpoint pathway is an efficient immunotherapeutic modality that provided significant advances in cancer treatment especially in solid tumors highly resistant to traditional therapy. Monoclonal antibodies (mAbs) and small-molecule inhibitors are the two main strategies used to block this axis with mAbs suffering from many limitations. Accordingly, the current alternative is the development of small-molecule PD-1/PD-L1 inhibitors. Here, we present a sequential virtual screening (VS) protocol involving pharmacophore screening followed by molecular docking for the discovery of novel PD-L1 inhibitors. The VS protocol resulted in the discovery of eight novel compounds. A 100 ns MD simulation showed two compounds, H4 and H6, exhibiting a stable binding mode at the PD-L1 dimer interface. Upon evaluation of their immunological activities, the two compounds induced higher cytokines levels (IL-2, IL-6, and INF-γ) relative to BMS-202, 72 h post treatment of PBMCs of HCC patients. Thus, the discovered hits represent potential leads for the development of novel classes targeting the PD-L1 receptor as anti-hepatocellular carcinoma agents.
Insights
Researchers discovered novel small-molecule inhibitors targeting the PD-1/PD-L1 pathway for cancer immunotherapy. Two compounds, H4 and H6, showed promising results in preclinical models, potentially leading to new treatments for hepatocellular carcinoma.
Area of Science:
- Oncology
- Immunotherapy
- Drug Discovery
Background:
- The programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) pathway is a key target for cancer immunotherapy, particularly for solid tumors resistant to conventional treatments.
- Monoclonal antibodies (mAbs) are currently used to block this pathway, but they have limitations.
- Small-molecule inhibitors offer a promising alternative for PD-1/PD-L1 blockade.
Purpose of the Study:
- To develop a virtual screening protocol for identifying novel small-molecule inhibitors of PD-L1.
- To discover and characterize new compounds targeting the PD-L1 receptor for potential anti-cancer applications.
Main Methods:
- A sequential virtual screening (VS) approach combining pharmacophore screening and molecular docking was employed.
- Molecular dynamics (MD) simulations were performed to assess the stability of identified compounds.
- Immunological activity was evaluated by measuring cytokine levels in peripheral blood mononuclear cells (PBMCs) from hepatocellular carcinoma (HCC) patients.
Main Results:
- The VS protocol successfully identified eight novel compounds with potential PD-L1 inhibitory activity.
- Two compounds, H4 and H6, demonstrated stable binding to the PD-L1 dimer interface through MD simulations.
- Compounds H4 and H6 induced significantly higher levels of cytokines (IL-2, IL-6, and INF-γ) compared to BMS-202 in HCC patient PBMCs.
Conclusions:
- The identified compounds H4 and H6 represent promising lead candidates for developing novel small-molecule PD-L1 inhibitors.
- These compounds hold potential as therapeutic agents for hepatocellular carcinoma by modulating the immune checkpoint pathway.
