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

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, P18 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, P18 promoted HepG2 cell death dose dependently in a HepG2/PD-L1
and Jurkat/PD-1 coculture cell model. Further, P18 demonstrated
significantly higher water solubility (17.61 mg/mL) and improved pharmacokinetics
(e.g., t1/2 of ∼20
h and oral bioavailability of 12%) than the previous analogues. Moreover, P18 was highly effective in suppressing tumor growth in an
immune checkpoint humanized mouse model without apparent toxicity.
Collectively, these results suggest that compound P18 represents a promising PD-1/PD-L1 inhibitor worthy of further investigation
as a potential anticancer agent.