Symmetry-based ligand design and evaluation of small molecule inhibitors of programmed cell death-1/programmed death-ligand 1 interaction |
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| Affiliation: | 1. Chemical Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan;2. Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan;1. Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, PR China;2. Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, 110016, PR China;3. College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150086, PR China;4. Chinese People’s Liberation Army Logistics Support Force No. 967 Hospital, Dalian, 116021, PR China;1. Lab of Chemical Biology and Molecular Drug Design, College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, China;2. Institute of Drug Development & Chemical Biology, Zhejiang University of Technology, Hangzhou 310014, China;3. Lab of Molecular Immunology, Virus Inspection Department, Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou 310051, China;1. College of Pharmacy, Graduate School of Pharmaceutical Sciences, Global Top5 Research Program, Ewha Womans University, Seoul 120-750, Republic of Korea;2. College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Republic of Korea;3. College of Pharmacy, CHA University, Pocheon 487-010, Republic of Korea;1. Department of Biochemistry, Vanderbilt University, Nashville, TN 37232-0146, USA;2. Vanderbilt Institute of Chemical Biology Synthesis Core, Vanderbilt University, Nashville, TN 37232-0146, USA;1. OncoWitan, Lille (Wasquehal) 59290, France;2. University of Lille, CNRS UMR 8576, Unité de Glycobiologie Structurale et Fonctionnelle, 59000 Lille, France |
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| Abstract: | ![]()
The development of small molecule inhibitors of PD-1/PD-L1 is eagerly anticipated for treatment of cancer. We focused on the symmetry of the ternary complex structure of reported small molecule ligands and hPD-L1 homodimers, and designed partially- or fully-symmetric compounds for more potent inhibitors. The design of the new compounds was guided by our hypothesis that the designed symmetric compound would induce a flip of sidechain of ATyr56 protein residue to form a new cavity. The designed compound 4 exhibited substantially increased binding affinity to hPD-L1, as well as PD-1/PD-L1 inhibitory activity in physiological conditions. Compound 4 also showed a dose-dependent increase in IFN-γ secretion levels in a mixed lymphocyte reaction assay. These results not only indicate the feasibility of targeting the PD-1/PD-L1 pathway with small molecules, but illustrate the applicability of the symmetry-based ligand design as an attractive methodology for targeting protein-protein interaction stabilizers. |
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| Keywords: | PD-1 PD-L1 Small-molecules Immune checkpoint inhibitor Surface plasmon resonance Drug design |
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