The PD-1/PD-L1 immune checkpoint pathway is a clinically validated drug target engaged in the suppression of tumor immunity. Despite the clinical success of antibodies in patients with advanced cancers, there are currently no FDA-approved small molecule immunomodulators for this immune checkpoint pathway. Small molecules offer an appropriate pharmacokinetic profile for oral administration, increased tumor penetration, and shorter half-life for management of intractable immune-related side effects. Here, we present our design, synthesis, and a preliminary structure-activity relationship study of a series of C2-symmetric inhibitors. Based on structural studies, the C2-symmetric inhibitor LH1307 (2b) directly bound to PD-L1 and induced the formation of a near symmtrically arranged PD-L1 homodimer. LH1307 demonstrated an IC50 of 3 nM in a homogeneous time resolved fluorescence assay. In a cell-based PD-1/PD-L1 blockade assay, LH1306 (2a) and LH1307 were found to be about 8.2- and 2.8-fold more potent in inhibiting the PPI as compared to LH1301 (1a) and LH1305 (1b), respectively. The new C2-symmetric inhibitors could serve as new leads for further optimization into potential immunomodulators for the treatment of cancer.

Design, synthesis, evaluation and X-ray structure of small molecule inhibitors of the programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) protein-protein interaction

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.