Design, synthesis and activity evaluation of tetrahydroisoquinoline‐based programmed cell death ligand 1 inhibitors

Abstract Small molecule blockade of the programmed death receptor 1 (PD‐1)/programmed cell death ligand 1 (PD‐L1) pathway represents a promising approach for tumor immunotherapy. Based on the previously developed 3D‐quantitative structure‐activity relationship pharmacophore model for PD‐L1 inhibitors, virtual screening followed by homogeneous time‐resolved fluorescence (HTRF) activity testing identified the compound {1‐[(biphenyl‐4‐yl)methyl]‐7‐methoxy‐1,2,3,4‐tetrahydroisoquinolin‐6‐yl}acetic acid methyl ester (Compound Y6 ) as a hit. Analysis of computational docking results of compound Y6 with PD‐L1 suggested targeting the methyl acetate substituent at position 6 for optimization. Guided by this, 20 new derivatives were designed and synthesized. The synthesized compounds were subjected to HTRF test and 6 compounds with significant protein blocking effects were screened for subsequent surface plasmon resonance (SPR) test. Subsequent SPR analysis confirmed strong binding of these 6 compounds to hPD‐L1 protein with K D values ranging from 0.24 to 21.31 μM. Several derivatives displayed improved or comparable PD‐L1 binding affinity relative to the lead compound Y6 ( K D = 11.3 μM). A co‐incubation system (PD‐1 + Jurkat T/PD‐L1 + HepG2) was established to evaluate functional immune restoration. This evaluation revealed that compound Y7f effectively promoted HepG2 cells death by restoring T cell immune function. MD simulations identify (1R,16R)‐Y7f as the most potent PD‐L1 dimerization inducer within the compound Y7f stereoisomer series. The results indicated that the biphenyl‐tetrahydroisoquinoline scaffold is a promising structural framework for developing novel PD‐1/PD‐L1 inhibitors and deserves further investigation.