TY - JOUR
T1 - Design, synthesis, evaluation, and structural studies of C2-Symmetric Small molecule inhibitors of programmed cell death-1/programmed death-ligand 1 protein-protein interaction
AU - Basu, Subhadwip
AU - Yang, Jeffrey
AU - Xu, Bin
AU - Magiera-Mularz, Katarzyna
AU - Skalniak, Lukasz
AU - Musielak, Bogdan
AU - Kholodovych, Vladyslav
AU - Holak, Tad A.
AU - Hu, Longqin
N1 - Funding Information: We thank the Center for Integrative Proteomics Research (CIPR), Rutgers University, for performing the HRMS experiments and Eurofins DiscoverX for testing the small molecules in their PathHunter cell-based PD-1 signaling assay. This research was partially funded (to T.A.H.) by project no. POIR.04.04.00-00-420F/17-00, which is carried out within the TEAM programme of the Foundation for Polish Science cofinanced by the European Union under the European Regional Development Fund. K.M.M. is a recipient of the START fellowship from the Foundation for Polish Science (FNP). B.X. was a recipient of a visiting scholarship from the College of Chemistry and Molecular Engineering, Nanjing Tech University (Nanjing, China). We acknowledge the MCB Structural Biology Core Facility (supported by the TEAM TECH CORE FACILITY/2017-4/6 grant from the Foundation for Polish Science) for valuable support. Publisher Copyright: © 2019 American Chemical Society.
PY - 2019/8/8
Y1 - 2019/8/8
N2 - A series of C2-symmetric inhibitors was designed and evaluated for inhibitory activity against the programmed cell death-1/programmed death-ligand 1(PD-1/PD-L1) protein-protein interaction (PPI) in a homogenous time-resolved fluorescence (HTRF) assay and PD-1 signaling in cell-based coculture assays. C2-symmetric inhibitors 2a (LH1306) and 2b (LH1307) exhibited IC50 values 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 coculture 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 cocrystal 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 that previously reported for other inhibitors.
AB - A series of C2-symmetric inhibitors was designed and evaluated for inhibitory activity against the programmed cell death-1/programmed death-ligand 1(PD-1/PD-L1) protein-protein interaction (PPI) in a homogenous time-resolved fluorescence (HTRF) assay and PD-1 signaling in cell-based coculture assays. C2-symmetric inhibitors 2a (LH1306) and 2b (LH1307) exhibited IC50 values 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 coculture 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 cocrystal 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 that previously reported for other inhibitors.
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U2 - https://doi.org/10.1021/acs.jmedchem.9b00795
DO - https://doi.org/10.1021/acs.jmedchem.9b00795
M3 - Article
C2 - 31298541
VL - 62
SP - 7250
EP - 7263
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 15
ER -