Discovery of Novel and Highly Potent Resorcinol Dibenzyl Ether-Based PD-1/PD-L1 Inhibitors with Improved Drug-like and Pharmacokinetic Properties for Cancer Treatment

Abstract

A series of programmed cell death-1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors based on the resorcinol diphenyl ether scaffold were discovered by incorporating hydrophilic moieties into the side chain and converting into the corresponding hydrochloride salt. Among these compounds, <b>P18</b> showed the highest inhibitory activity against PD-1/PD-L1 with an IC₅₀ value of 9.1 nM in a homogeneous time-resolved fluorescence binding assay. Besides, <b>P18</b> promoted HepG2 cell death dose dependently in a HepG2/PD-L1 and Jurkat/PD-1 coculture cell model. Further, <b>P18</b> demonstrated significantly higher water solubility (17.61 mg/mL) and improved pharmacokinetics (<i>e.g.</i>, <i>t</i>_1/2 of ∼20 h and oral bioavailability of 12%) than the previous analogues. Moreover, <b>P18</b> was highly effective in suppressing tumor growth in an immune checkpoint humanized mouse model without apparent toxicity. Collectively, these results suggest that compound <b>P18</b> represents a promising PD-1/PD-L1 inhibitor worthy of further investigation as a potential anticancer agent.