Flurbiprofen as a biphenyl scaffold for the design of small molecules binding to PD-L1 protein dimer

Small molecules targeting the PD-1/PD-L1 immune checkpoint are actively searched to offer anticancer oral treatment modalities. Different small molecules have been designed, such as BMS-202 and BMS-1166 which potently bind to PD-L1, sequestering the protein dimer and thus preventing cancer cells to escape antitumor immune responses. A (top -> down) deconvolution of BMS compounds has characterized their central biphenyl unit as the minimal element required for PD-L1 protein binding. On this basis, we searched for approved drugs containing a similar biphenyl unit and endowed with immune modulatory activities. We identified the biphenyl anti-inflammatory drug flurbiprofen (FLB) as a potential candidate for PD-L1 interaction, and then proposed a (bottom -> up) convolution to select similar molecules, used in Human, susceptible to engage stable interactions with PD-L1. The hypothesis was tested by molecular modeling using the crystal structure of BMS-202 bound to the PD-L1 dimer. The calculations suggest that both (R) and (S) isomers of FLB can form stable complexes with PD-L1, penetrating deep into the cylindric pocket at the interface of the protein dimer. However, the potential energy of interaction (Delta E) is reduced by similar to 40% for FLB compared to BMS compounds. Then, we identified three FLB analogues (diflunisal, CHF-5074 and HCT1026) forming stable complexes with PD-L1. The longer FLB derivative HCT1026 appears as a suitable binder of the PD-L1 dimer, sliding well along the BMS binding cavity. Our approach proposes a new strategy to discover PD-L1-binding small molecules and raises the intriguing possibility that FLB can bind transiently to PD-L1, thus possibly explaining some of its biological effects. Our study opens new perspectives for the use of FLB (and analogs) as an immune modulator in oncology and other therapeutic domains.