Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University) , Ministry of Education , 103 Wenhua Road , Shenyang 110016 , PR China.
Department of Pharmacology , Shenyang Pharmaceutical University , 103 Wenhua Road , Shenyang 110016 , PR China.
J Med Chem. 2019 May 9;62(9):4703-4715. doi: 10.1021/acs.jmedchem.9b00312. Epub 2019 Apr 19.
Inhibition of the programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) interaction using small-molecule inhibitors is an emerging immunotherapeutic approach. A novel series of [1,2,4]triazolo[4,3- a]pyridines were designed and found to be potent inhibitors of the PD-1/PD-L1 interaction. Among them, compound A22 exhibited the most potent activity, as assessed by homogenous time-resolved fluorescence assay, with an IC of 92.3 nM. Furthermore, A22 dose-dependent elevated interferon-γ production in a co-culture model of Hep3B/OS-8/hPD-L1 and CD3 T cells. We concluded that A22 is a promising lead compound for the development of inhibitors of the PD-1/PD-L1 interaction. In addition, we explored the structure-activity relationships of the newly synthesized [1,2,4]triazolo[4,3- a]pyridines and demonstrated that a ring fusion strategy can be employed for designing analogues of the Bristol-Myers Squibb chemical series. These studies pave the way for future drug design.
使用小分子抑制剂抑制程序性细胞死亡-1（PD-1）/程序性细胞死亡配体 1（PD-L1）的相互作用是一种新兴的免疫治疗方法。设计了一系列新型[1,2,4]三唑并[4,3-a]吡啶，并发现它们是 PD-1/PD-L1 相互作用的有效抑制剂。其中，化合物 A22 在 Hep3B/OS-8/hPD-L1 和 CD3 T 细胞共培养模型中通过均相时间分辨荧光测定评估，具有最强的活性，IC 为 92.3 nM。此外，A22 呈剂量依赖性增加干扰素-γ的产生。我们得出结论，A22 是开发 PD-1/PD-L1 相互作用抑制剂的有前途的先导化合物。此外，我们还探索了新合成的[1,2,4]三唑并[4,3-a]吡啶的构效关系，并证明环融合策略可用于设计 Bristol-Myers Squibb 化学系列的类似物。这些研究为未来的药物设计铺平了道路。
