Improving tumor sensitivity by the introduction of an ester chain to triaryl derivatives targeting PD-1/PD-L1

PD-1/PD-L1 pathway blockade is a promising immunotherapy for the treatment of cancer. In this manuscript, a series of triaryl compounds containing ester chains were designed and synthesized based on the pharmacophore studies of the lead BMS-1. After several SAR iterations, 22 showed the best biochemical activity binding to hPD-L1 with an IC50 of 1.21 nM in HTRF assay, and a KD value of 5.068 nM in SPR analysis. Cell-based experiments showed that 22 effectively promoted A549 cell death by restoring T-cell immune function. 22 showed significant in vivo antitumor activity in a 4T1 mouse model without obvious toxicity, with a TGI rate of 67.8 % (20 mg/kg, ip). Immunohistochemistry data indicated that 22 activates the immune activity in tumors. These results suggest that 22 is a promising compound for further development of PD-1/PD-L1 inhibitor for cancer therapy. [Display omitted] •Synthesis of a series of novel triaryl derivatives containing ester chains.•22 Showed the best biochemical activity binding to hPD-L1 with an IC50 of 1.21 nM.•22 effectively promoted A549 cell death by restoring T cell immune function.•22 showed significant in vivo antitumor activity in a 4T1 mouse model.