Design, Synthesis, Evaluation, and SAR of 5-Phenylisoindoline Derivatives, a Potent Class of Small-Molecule Inhibitors Targeting the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 (PD-1/PD-L1) Interaction.

A novel series of 5-phenylisoindoline derivatives were designed, synthesized, and evaluated for their activity to inhibit the interaction of PD-1/PD-L1 through the homogeneous time-resolved fluorescence assay. Meanwhile, structure-activity relationships were discussed according to both experiments and calculations. Several compounds exhibited potent activity with an IC50 value less than 10 nM, especially D6 (4.8 nM). D6 could promote IFN-γ secretion and reduce the proportion of PD-L1 late apoptosis at 100 nM in the coculture model of peripheral blood mononuclear cells and hPD-L1-FC. Beyond this, the in vitro model showed D6 could lead to the weakening of migration caused by the PD-1/PD-L1 axis. Furthermore, D6 also displayed dose-dependent and low-toxic efficacy in the MC38 mouse tumor model with the tumor growth inhibition of 52.8% (20 mg/kg, ip) and 64.4% (160 mg/kg, i.g.). Mechanistic investigations suggested that D6 could activate the immune microenvironment in the tumor. Thus, D6 is a promising small molecule lead for blocking PD-1/PD-L1.