1. Design, synthesis, pharmacological evaluation, and computational study of benzo[d] isothiazol-based small molecule inhibitors targeting PD-1/PD-l1 interaction.
- Author
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Wang H, Shen L, Chen L, Gao Y, Ma L, Lian W, Zhang Z, Liu H, Yang H, Wang J, Zhao D, and Cheng M
- Subjects
- Humans, Structure-Activity Relationship, Molecular Structure, Dose-Response Relationship, Drug, Small Molecule Libraries pharmacology, Small Molecule Libraries chemistry, Small Molecule Libraries chemical synthesis, Jurkat Cells, Molecular Docking Simulation, Thiazoles pharmacology, Thiazoles chemistry, Thiazoles chemical synthesis, Animals, Benzothiazoles pharmacology, Benzothiazoles chemistry, Benzothiazoles chemical synthesis, Antineoplastic Agents pharmacology, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, B7-H1 Antigen metabolism, B7-H1 Antigen antagonists & inhibitors, Programmed Cell Death 1 Receptor antagonists & inhibitors, Programmed Cell Death 1 Receptor metabolism, Drug Design
- Abstract
Blockade of the programmed cell death-1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway is an attractive strategy for immunotherapy, but the clinical application of small molecule PD-1/PD-L1 inhibitors remains unclear. In this work, based on BMS-202 and our previous work YLW-106, a series of compounds with benzo[d]isothiazol structure as scaffold were designed and synthesized. Their inhibitory activity against PD-1/PD-L1 interaction was evaluated by a homogeneous time-resolved fluorescence (HTRF) assay. Among them, LLW-018 (27c) exhibited the most potent inhibitory activity with an IC
50 value of 2.61 nM. The cellular level assays demonstrated that LLW-018 exhibited low cytotoxicity against Jurkat T and MDA-MB-231. Further cell-based PD-1/PD-L1 blockade bioassays based on PD-1 NFAT-Luc Jurkat cells and PD-L1 TCR Activator CHO cells indicated that LLW-018 could interrupt PD-1/PD-L1 interaction with an IC50 value of 0.88 μM. Multi-computational methods, including molecular docking, molecular dynamics, MM/GBSA, MM/PBSA, Metadynamics, and QM/MM MD were utilized on PD-L1 dimer complexes, which revealed the binding modes and dissociation process of LLW-018 and C2 -symmetric small molecule inhibitor LCH1307. These results suggested that LLW-018 exhibited promising potency as a PD-1/PD-L1 inhibitor for further investigation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Masson SAS.)- Published
- 2024
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