Negative Immune Checkpoint Inhibitors.

Checkpoint inhibitors are a modern therapeutic approach for treating various types of cancer, metabolic diseases, and chronic infections. The main goal of this therapy is to specifically unlock the immune system, allowing it to recognize and eliminate cancer cells or pathogens, primarily through the activation of T lymphocytes. Monoclonal antibodies used in the treatment of various cancers, such as pembrolizumab (Keytruda), nivolumab (Opdivo), and ipilimumab (Yervoy), carry several limitations, primarily due to their large molecular size. The main challenges include limited tissue penetration, long half-life in the body, and the risk of autoimmune responses. Compared to antibodies, small-molecule and peptide inhibitors offer significant advantages related to their molecular structure. These drugs demonstrate a better ability to penetrate hard-to-reach areas, such as the tumor microenvironments, can be administered orally, and often show lower immunogenicity. A new generation of drugs is PROTACs, which combine the ability to direct proteins to degradation with the action of checkpoint inhibitors, contributing to the elimination of proteins responsible for suppressing the immune response. This publication describes small-molecule inhibitors, peptide inhibitors, and PROTAC molecules targeting negative immune checkpoints-CTLA-4, PD-1, VISTA, TIM-3, BTLA-4, LAG-3, and TIGIT.