Discovery of Potentiating Agents for Cancer Immunotherapy Targeting the Mechanism of IFN-gamma Activation

Abstract

Immuno-anticancer therapies that restore and improve the body's immune system to identify and attack tumor cells have minor side effects than traditional treatments. Immune checkpoint inhibitors among immune anticancer therapeutic agents differ depending on cancer types, but they have a limitation of low initial response rate. Previous studies confirmed that activation of the IFN-gamma signaling pathway increases the responsiveness of immune checkpoint inhibitors. I would like to suppress the activity of protein A discovered by genome-wide CRISPR screening and reduce resistance to immune checkpoint inhibitors through activation of the IFN-gamma signaling pathway. I selected 5 compounds with concentration-dependent inhibitory activity by AI algorithm and in-vitro analysis. I synthesized 14 derivatives of one of them, LDD-4650. Compound 8b was found to be active in protein-based assays and have a concentration-dependent increase in the IFN-gamma signaling pathway in cell-based assays. In this study, I demonstrated the possibility of activating the IFN-gamma signaling pathway through protein A inhibition, thereby increasing the responsiveness of immune checkpoint inhibitors.