A comparative study of the recent most potent small-molecule PD-L1 inhibitors: what can we learn?

Immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway have become a “game-changer” in cancer treatment. However, none of small molecular has been approved yet. To explore advantages and disadvantages various scaffolds, different biological evaluations were performed on three selected inhibitors, namely Incyte-001, Incyte-011, BMS-1001. In HTRF assay, BMS-1001 showed best binding activity for PD-L1 (IC50 = 0.9 nM) while Incyte-011 (IC50 = 5.293 nM) was twice more potent than Incyte-001 (IC50 = 11 nM). Also, only increased IFN-γ production. Notably, exhibited highest cytotoxicity (EC50 = 1.635 μM). Interestingly, (injected intravenously 2 mg/kg) also displayed good blood-brain barrier permeability reached high concentration brain tissue. Finally, docking modeling studies suggested that compounds bind pocket at interface two monomers. Overall, our work shows characteristics depending their unique skeletons, which can be further improved to better clinical application.