Synthesis and evaluation of indole-containing derivatives as C-linked PD-L1 inhibitors for cancer immunotherapy

•A series of indole derivatives were synthesized and structurally characterized.•Compound 16 showed a much higher PD-1/PD-L1 inhibitory potential compared to other compounds.•Compounds 16, 17 and 21 could increase the cytotoxic potency of CD8+ t cells to kill human NSCLC cells.•Docking results suggested that indole derivatives formed π-π stacking with the tyr 56 and showed hydrophobic interactions with the residues of ile 54 and val 68. Discovery and development of novel small molecules targeting PD-1/PD-L1 axis represent a promising approach to fight against cancers. Herein, we report the synthesis, characterization and evaluation of indole derivatives with novel molecular architectures as PD-L1 inhibitors for cancer immunotherapy. Structure based design together with preliminary biological evaluation of indole derivatives resulted in the identification of 4-((5‑methoxy-3-((2-methyl-[1,1′-biphenyl]-3-yl)methyl)-1H-indol-1-yl)methyl)benzonitrile (16) with an IC50 value of 46 nM. Compound 16 was demonstrated to be a highly potent hPD-L1 inhibitor in its ability to block PD-1/PD-L1 interaction. Compound 16 effectively promoted hPD-L1 to undergo non-covalent aggregation and enhanced the cellular cytotoxicity of CD8+ T cell to hNSCLC cell. Docking results suggested that indole ring in each of compounds could form a strong π-π stacking with the Tyr 56 residue that was a critical amino acid on the surface of PD-L1 for PD-1/PD-L1 interaction. The presence of R2 group in each of indole derivatives appeared to further enhance the PD-1/PD-L1 inhibitory potential through hydrophobic interactions with the residues of Ile 54 and Val 68. [Display omitted]