National Engineering Research Center for the Emergency Drug, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and ToxicologyBeijing 100850, China.
J Med Chem. 2020 Nov 25;63(22):13825-13850. doi: 10.1021/acs.jmedchem.0c01329. Epub 2020 Nov 13.
A series of novel linear aliphatic amine-linked triaryl derivatives as inhibitors of PD-1/PD-L1 were designed, synthesized, and evaluated in vitro and in vivo. In this chemical series, compound showed the most potent inhibitory activity and binding affinity with hPD-L1, with an IC value of 12 nM and a KD value of 16.2 pM, showing a binding potency approximately 2000-fold that of hPD-1. Compound could bind with hPD-L1 on the cellular surface and competitively block the interaction of hPD-1 with hPD-L1. In a T cell function assay, restored the T cell function, leading to increased IFN-γ secretion. Moreover, in a humanized mouse model, compound significantly inhibited tumor growth without obvious toxicity and showed moderate PK properties after intravenous injection. These results indicated that is a promising lead for further development of small-molecule PD-1/PD-L1 inhibitors for cancer therapy.
一系列新型的线性脂肪族胺连接的三芳基衍生物被设计、合成并在体外和体内进行了评估，作为 PD-1/PD-L1 的抑制剂。在这个化学系列中，化合物 表现出最有效的抑制活性和与 hPD-L1 的结合亲和力，IC 值为 12 nM，KD 值为 16.2 pM，其结合效力大约是 hPD-1 的 2000 倍。化合物 可以与细胞表面上的 hPD-L1 结合，并竞争性地阻断 hPD-1 与 hPD-L1 的相互作用。在 T 细胞功能测定中，化合物 恢复了 T 细胞功能，导致 IFN-γ 分泌增加。此外，在人源化小鼠模型中，化合物 显著抑制肿瘤生长，没有明显的毒性，并且在静脉注射后表现出中等的 PK 特性。这些结果表明，化合物 是进一步开发用于癌症治疗的小分子 PD-1/PD-L1 抑制剂的有前途的先导化合物。
