Discovery of [1,2,4]Triazolo[4,3- a]pyridines as Potent Inhibitors Targeting the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 Interaction

  • J Med Chem. 2019 May 9;62(9):4703-4715. doi: 10.1021/acs.jmedchem.9b00312.
Mingze Qin  1 ,  Qi Cao  1 ,  Shuaishuai Zheng  1 ,  Ye Tian  1 ,  Haotian Zhang  2 ,  Jun Xie  2 ,  Hongbo Xie  3 ,  Yajing Liu  1 ,  Yanfang Zhao  1 ,  Ping Gong  1
Affiliations
  • 1. Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University) , Ministry of Education , 103 Wenhua Road , Shenyang 110016 , PR China.
  • 2. Department of Pharmacology , Shenyang Pharmaceutical University , 103 Wenhua Road , Shenyang 110016 , PR China.
  • 3. College of Bioinformatics Science and Technology , Harbin Medical University , Harbin 150086 , PR China.
PMID: 30964291 DOI: 10.1021/acs.jmedchem.9b00312
Abstract

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-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.

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