SAR study of small molecule inhibitors of the programmed cell death‐1/programmed cell death‐ligand 1 interaction
| Autor: | Kyoko Fukushima, Rie Hantani, Shiori Naruoka, Yukiyo Toyonaga, Yuji Hori, Koichi Aoyagi, Hiroshi Yamanaka, Susumu Miyazaki, Atsuo Tanimoto, Seiji Kawashita, Yoshiji Hantani |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Pyridines
Stereochemistry Cell Antineoplastic Agents Apoptosis Ether Crystallography X-Ray Ligands Biochemistry B7-H1 Antigen Small Molecule Libraries Structure-Activity Relationship chemistry.chemical_compound Neoplasms PD-L1 Acetamides Drug Discovery medicine Humans Structure–activity relationship Pharmacology Ligand efficiency Molecular Structure biology Chemistry Organic Chemistry Small molecule Receptor–ligand kinetics Molecular Docking Simulation medicine.anatomical_structure biology.protein Thermodynamics Molecular Medicine Linker Protein Binding Signal Transduction |
| Zdroj: | Chemical Biology & Drug Design. 98:914-929 |
| ISSN: | 1747-0285 1747-0277 |
| DOI: | 10.1111/cbdd.13949 |
| Popis: | The development of small molecule inhibitors of programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) has drawn research interest for the treatment of cancer. Recently, we reported the discovery of a novel dimeric core small molecule PD-1/PD-L1 inhibitor. In an effort to discover more potent inhibitors, we further explored the dimeric core scaffold. Our investigations of the structure-activity-relationship revealed that introduction of lipophilic substituents onto one of the di-alkoxylated phenyl rings improved binding affinities to PD-L1, and inhibitory activities of PD-1/PD-L1 in cellular assays. Furthermore, conversion of the ether linker part to an olefin linker not only improved binding affinity but also led to slow dissociation binding kinetics. We also explored more potent, as well as downsized, scaffolds. Compounds bearing a linear chain in place of one of the di-alkoxylated phenyl rings exhibited good binding affinity with improved ligand efficiency (LE). Representative compounds demonstrated potent inhibitory activities of PD-1/PD-L1 in the submicromolar range in cellular assays as well as cellular function in the mixed lymphocyte reaction (MLR) assay with efficacy comparable to anti-PD-1 antibody. Our results provide applicable information for the design of more potent inhibitors targeting PD-1/PD-L1 pathway. |
| Databáze: | OpenAIRE |
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