6rpg

Publication Abstract from PubMed

A series of C2-symmetric inhibitors was designed and evaluated for inhibitory activity against the PD-1/PD-L1 protein-protein interaction (PPI) in a homogenous time-resolved fluorescence (HTRF) assay and PD-1 signaling in cell-based co-culture assays. C2-symmetric inhibitors 2a (LH1306) and 2b (LH1307) exhibited IC50's of 25 and 3.0 nM, respectively, in the HTRF assay. While 2a was ~3.8-fold more potent than previously reported inhibitor 1a, 2b could not be differentiated from 1b due to their high potency and the limit of our HTRF assay conditions. In one cell-based co-culture PD-1 signaling assay, 2a and 2b were 8.2- and 2.8-fold more potent in inhibiting PD-1 signaling than 1a and 1b, respectively. NMR and X-ray co-crystal structural studies provided more structural insights into the interaction between 2b and PD-L1; 2b binds to PD-L1 at the PD-1 binding site and induces the formation of a more symmetrically arranged PD-L1 homodimer than previously reported for other inhibitors.

Design, synthesis, evaluation and structural studies of C2-symmetric small molecule inhibitors of the programmed cell death-1/programmed death-ligand 1 (PD-1/PD-L1) protein-protein interaction.,Basu S, Yang J, Xu B, Magiera-Mularz K, Skalniak L, Musielak B, Kholodovych V, Holak TTA, Hu L J Med Chem. 2019 Jul 12. doi: 10.1021/acs.jmedchem.9b00795. PMID:31298541^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.