Załączony artykuł to wersja preprint. Wersja AAM ukaże się 2028-02-06
OnlineFirst 2026-02-06

Programmed Cell Death Protein-1 (PD-1)/Programmed Cell Death-Ligand 1 (PD-L1) interaction has a crucial role in maintaining the immune system's self-tolerance by downregulating T cell activation. This mechanism is also used by several types of cancers. By overexpressing the PD-L1 protein, cancer cells can evade the immune response and, therefore, become invisible to the immune system. Herein, we present a novel class of small molecular inhibitors targeting PD-L1 protein. Developed N-terphenylpicolinamides display high affinity to the molecular target. In our studies, we focused on in vitro-based SAR analysis utilizing Jurkat T cells expressing PD-1 co-cultured with CHO/TCRAct/hPD-L1 cells. Furthermore, for the most promising compound, we demonstrated that blocking the PD-1/PD-L1 interaction and subsequently activating immune cells leads to enhanced elimination of cancer cells from the co-culture. In our study, we were also able to rationalize the binding of the small molecule to the molecular target.