Rational design of D(+)-biotin-conjugated resorcinol dibenzyl ethers as tumor-targeted PD-L1 inhibitors for precision...

This study aims to discover and characterize novel D(+)-biotin-conjugated PD-L1 inhibitors for precision tumor-targeted cancer immunotherapy.

Integrated strategies, including computer-aided molecular simulation, antiproliferative activity (CCK8) assay, surface plasmon resonance (SPR), pharmacokinetic evaluation, and in vivo antitumor efficacy assessment, were performed.

Compound SW-1 showed potent and selective inhibitory activity against PD-1/PD-L1 interaction with an IC₅₀ of 5.6 nM, and high binding affinity to both human and murine PD-L1. Molecular docking and molecular dynamics simulations verified stable binding of SW-1 to the PD-L1 dimer interface with key intermolecular interactions. Pharmacokinetic studies in rats revealed favorable systemic exposure and a suitable half-life for in vivo application. In the B16-F10 melanoma mouse model, SW-1 achieved a more potent tumor growth inhibition (TGI = 64.9%) than the PD-L1 antibody (TGI = 44.2%), effectively promoted CD8⁺ T cell infiltration into the tumor microenvironment, and maintained favorable in vivo safety without obvious body weight loss.

SW-1, as a highly potent biotin-conjugated PD-L1 small-molecule inhibitor, exhibits outstanding target activity, favorable pharmacokinetic properties, potent antitumor efficacy, and high safety. These results highlight SW-1 as a promising lead candidate for further development in precision tumor-targeted immunotherapy.