Synthesis and preliminary evaluation of aminophenol derivatives as molecular glues blocking PD-1/PD-L1 interaction

Abstract

Discovery of novel small molecules blocking PD-1/PD-L1 interaction is a promising approach mobilizing immune system to fight against cancers. Herein we report the synthesis and identification of a series of aminophenol derivatives as a novel class of PD-1/PD-L1 inhibitors for cancer immunotherapy. Structure based design together with preliminary evaluation of each region of the molecular architecture resulted in identification of (R)-3-(5-chloro-2-((4-cyanobenzyl)oxy)-4-(((2-methyl-4′-(trifluoromethoxy)-[1,1′-biphenyl]-3-yl)methyl)amino)benzyl)-2-oxooxazolidine-4-carboxylic acid (11e) with an IC50 value of 21.3 nM. Compound 11e was demonstrated to be a highly potent hPD-L1 inhibitor and showed enhanced inhibitory potency compared to resorcinol derivative (compound 20). Compound 11e was capable of increasing the cytotoxic potency of CD8+ T cells with regard to killing human NSCLC cells.