Discovery of Small Molecule PD-L1 Inhibitors via Optimization of Solvent-Interaction Region for Cancer Immunotherapy

Despite extensive research, the topic of anti-PD-L1 small-molecule inhibitors remains elusive. Herein, we report the design, synthesis, and bioevaluation of a series of small molecule PD-L1 inhibitors via optimization of the solvent-interaction region. Among them, compound GJ19 showed the most potent anti-PD-L1 effects with an IC₅₀ of 32.06 nM in the HTRF (homogenous time-resolved fluorescence) assay, better than BMS-202 (IC₅₀ = 62.1 nM). In addition, the SPR (surface plasmon resonance) assay revealed that GJ19 can effectively bind to human/murine PD-L1 protein with K_D values of 171 and 290 nM, respectively. Furthermore, GJ19 concentration-dependently promoted HepG2 cell mortality in a co-culture model of HepG2/hPD-L1 and Jurkat T/hPD-1 cells. In the in vivo efficacy studies, GJ19 (intraperitoneal injection, 15 mg/kg) effectively suppressed tumor growth with a TGI of 56.8% in a B16-F10 melanoma mouse model by activating antitumor immunity. In conclusion, GJ19 represents a potential small molecule inhibitor of PD-L1, deserving further investigation for tumor immunotherapy.