Identification of LAMP2 as the direct target of aloperine derivatives for degrading PD-L1 through the lysosomal...

Aloperine derivatives can promote the degradation of PD-L1 through different pathways and elicit antitumor immunity, but their direct targets remain unclear. In this study, 30 aloperine derivatives were synthesized and screened for their efficacy in reducing PD-L1 levels, and compound 7a was found to effectively promote PD-L1 degradation through the lysosomal pathway. Then, based on the DeepDTAGen deep learning model, lysosome-associated membrane protein 2 (LAMP2) was predicted to be a potential functional target of 7a. Multiple biochemical assays demonstrated that 7a induced PD-L1 degradation through the LAMP2-mediated lysosomal pathway, with a K_D value of 5.58 μM. Furthermore, molecular docking and molecular dynamics simulations proposed a plausible binding mode of 7a with LAMP2. Therefore, the integrated computational-experimental strategy efficiently identified LAMP2 as a direct-binding functional target of 7a for the degradation of PD-L1 via lysosomal pathway, providing a reference case for the rapid discovery of target.