Journal of Medicinal Chemistry p. 4703 - 4715 (2019)
Update date:2022-08-16
Topics:
Qin, Mingze
Cao, Qi
Zheng, Shuaishuai
Tian, Ye
Zhang, Haotian
Xie, Jun
Xie, Hongbo
Liu, Yajing
Zhao, Yanfang
Gong, Ping
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 IC50 of 92.3 nM. Furthermore, A22 dose-dependent elevated interferon-γproduction 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.
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