Design, Synthesis, and Pharmacological Evaluation of Biaryl-Containing PD-1/PD-L1 Interaction Inhibitors Bearing a Unique Difluoromethyleneoxy Linkage

作者：Zilan Song, Bo Liu, Xia Peng, Wangting Gu, Yiming Sun, Xing Li, Yi Xu, Meiyu Geng, Jing Ai, Ao Zhang · 发表于：Journal of Medicinal Chemistry · 年份：2021 · DOI：10.1021/acs.jmedchem.1c01422 · 被引用次数：61 · 研究领域：Cancer Immunotherapy and Biomarkers、CAR-T cell therapy research、Peptidase Inhibition and Analysis

High Resolution Image Download MS PowerPoint Slide Blockade of immune checkpoint PD-1/PD-L1 has been a promising anticancer strategy; however, clinically available PD-1/PD-L1 small-molecule inhibitors are lacking. In view of the high potency of compound 2 (BMS-1002), structural fine tuning of the methoxy linkage together with diverse modification in the solvent interaction region was conducted. A series of novel derivatives featuring a difluoromethyleneoxy linkage were designed. Compound 43 was identified as the most promising PD-1/PD-L1 inhibitor with an IC 50 value of 10.2 nM in the HTRF assay. This compound is capable of promoting CD8 + T cell activation through inhibiting PD-1/PD-L1 cellular signaling. Moreover, in the Hepa1-6 syngeneic mouse model, administration of compound 43 at 1 mg/kg dosage promoted CD8 + T cell activation and delayed the tumor growth with good tolerance. Notably, the tumor in one mouse of the compound 43 -treated group was completely regressed. These results indicate that compound 43 is a promising candidate worthy of further investigation.