Discovery of novel indoline derivatives as potent small molecule PD-L1 inhibitors

The immune system plays a critical role in cancer control, but tumor cells often evade immune responses by exploiting inhibitory molecules like PD-1/PD-L1. Monoclonal antibodies targeting PD-1/PD-L1 interaction blockade have shown remarkable success in reactivating T-cell function in various advanced cancers, but they face limitations such as long half-life and immune-related adverse events (irAEs). In this study, we identified a new class of indoline-based scaffold through molecular docking analysis and synthesized derivatives, identifying compound 31 with an IC₅₀ of 0.89 nM in FRET assay. Compound 31 showed less than 50 % inhibition against CYP and hERG, and demonstrated moderate liver microsomal stability in mice. These results suggest that indoline derivatives may serve as potential PD-L1 inhibitors and warrant further investigation.