Recent Advances in the Development of PD-L1 Modulators: Degraders, Downregulators, and Covalent Inhibitors.

Therapeutic interference of the programmed cell death protein 1(PD-1)/immunosuppressive programmed cell death ligand 1 (PD-L1) signaling pathway by monoclonal antibodies has achieved spectacular success for treating various tumors. However, the development of small molecule inhibitors of PD-1/PD-L1 has lagged far behind due to the challenge of targeting the highly hydrophobic and relatively flat binding interface, despite the benefits small molecule can bring over therapeutic antibodies. This technical challenge provokes the adoption of different strategies in searching for small, medium-sized, and large molecule modulators (e.g., degraders, downregulators, and covalent inhibitors) of the PD-1/PD-L1 protein-protein interaction. In this review article, we discuss latest advances in the development of PD-L1 modulators, with a focus on degraders, downregulators, and covalent inhibitors.