A combined approach of structure‐based virtual screening and NMR to interrupt the PD‐1/PD‐L1 axis: Biphenyl‐benzimidazole containing compounds as novel PD‐L1 inhibitors

Immunotherapy has emerged as a game-changing approach for cancer treatment. Although monoclonal antibodies (mAbs) targeting the programmed cell death protein 1/programmed cell death protein 1 ligand 1 (PD-1/PD-L1) axis have entered the market revolutionizing the treatment landscape of many cancer types, small molecules, although presenting several advantages including the possibility of oral administration and/or reduced costs, struggled to enter in clinical trials, suffering of water insolubility and/or inadequate potency compared with mAbs. Thus, the search for novel scaffolds for both the design of effective small molecules and possible synergistic strategies is an ongoing field of interest. In an attempt to find novel chemotypes, a virtual screening approach was employed, resulting in the identification of new chemical entities with a certain binding capability, the most versatile of which was the benzimidazole-containing compound 10. Through rational design, a small library of its derivatives was synthesized and evaluated. The homogeneous time-resolved fluorescence (HTRF) assay revealed that compound 17 shows the most potent inhibitory activity (IC50) in the submicromolar range and notably, differently from the major part of PD-L1 inhibitors, exhibits satisfactory water solubility properties. These findings highlight the potential of benzimidazole-based compounds as novel promising candidates for PD-L1 inhibition.A virtual screening led to the discovery of new chemicals against the programmed cell death protein 1/programmed cell death protein 1 ligand 1 (PD-1/PD-L1) axis, including the versatile benzimidazole EML258 (10). A small library of this hit was created through thoughtful design. Compound 17 stood out with stronger inhibitory activity and impressive water solubility, setting it apart from most PD-L1 inhibitors. These results emphasize the potential of benzimidazole-based compounds as promising candidates for PD-L1 inhibition.image