Chlorophenylpyrazolone derivatives as novel PD-L1-targeted inhibitors of the PD-1/PD-L1 immune checkpoint.

Immune checkpoint inhibitors have emerged as one of the most promising approaches for cancer immunotherapy. Several injectable monoclonal antibodies targeting the programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) pathway are used to treat solid tumors. The development of orally active small molecules remains a challenge. In this context, we describe new pyrazolone derivatives bearing a chlorophenyl moiety aimed at targeting PD-L1 dimers. Ten new compounds with nanomolar affinities for PD-L1 were identified and among them, six were able to reactivate proliferation of CTLL-2 cytotoxic T-cells. The best compounds were further characterized for their capacity to modulate PD-L1 dimerization and their interaction with PD-L1 dimers, by microscale thermophoresis and molecular docking, respectively. Novel symmetric bis-pyrazolones with a high affinity for PD-L1 protein were also obtained. The 2,4-dichlorophenylpyrazolone scaffold offers novel perspectives to design PD-L1-targeting agents for the treatment of cancer.