Discovery and development of small-molecule inhibitors targeting cytotoxic T lymphocyte associated protein 4 to enhance cancer immunotherapy and reduce side effects.
TL;DR
D11 and A9 compounds were found to be effective at inhibiting tumor growth and prolonging survival in mouse models expressing humanised CTLA-4, highlighting their ability to overcome the limitations of anti-CTLA-4 antibodies.
Abstract
The immune system plays crucial role to fight against cancer. Still, cancer cells have evolved mechanisms to evade immune responses, especially through immune checkpoint proteins such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed death-ligand 1 (PD-L1). These checkpoints inhibit T-cell activation and are involved in immune tolerance in the tumor microenvironment. Checkpoint inhibitor-based immunotherapy, such as anti-CTLA-4 therapy, has transformed cancer care, but there are still unresolved issues concerning its safety and effectiveness, as well as immune-related adverse events (irAEs). To overcome these drawbacks, we considered using small-molecule CTLA-4 inhibitors instead of antibodies. To screen a library of 10 million compounds to identify small molecules that could bind to a specific site on the CTLA-4 protein and interfere with its interaction with CD80, we applied artificial intelligence (AI) in this research. This screening identified promising compounds, which were subsequently evaluated in vitro using AlphaLISA and luciferase reporter assays. These findings showed that the D11 and A9 compounds were capable of blocking the interaction between CTLA-4 and CD80 and had a desirable biosafety profile relative to conventional antibody-based treatments such as ipilimumab. Moreover, D11 and A9 were found to be effective at inhibiting tumor growth and prolonging survival in mouse models expressing humanised CTLA-4, highlighting their ability to overcome the limitations of anti-CTLA-4 antibodies. Also, we discovered in our research that the combination of D11 and anti-PD-1 therapy increased the therapeutic efficacy and did not lead to severe adverse reactions. These data suggest that small molecules can be a new and more efficient alternative to existing immune checkpoint inhibitors, with greater specificity and fewer adverse events.