Novel Biphenyl Pyridines as Potent Small-Molecule Inhibitors Targeting the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 Interaction

Tianyu Wang, Shi Cai, Mingming Wang, Wanheng Zhang, Kuojun Zhang, Dong Chen, Zheng Li, Sheng Jiang

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

With the successful clinical application of anti-programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) monoclonal antibodies (mAb), targeting the PD-1/PD-L1 interaction has become a promising method for the discovery of cancer therapy. Due to the inherent limitations of antibodies, it is necessary to search for small-molecule inhibitors against the PD-1/PD-L1 axis. We report the design, synthesis, and evaluation in vitro and in vivo of a series of novel biphenyl pyridines as the inhibitors of PD-1/PD-L1. 2-(((2-Methoxy-6-(2-methyl-[1,1′-biphenyl]-3-yl)pyridin-3-yl)methyl)amino)ethan-1-ol (24) was found to inhibit the PD-1/PD-L1 interaction with an IC50 value of 3.8 ± 0.3 nM and enhance the killing activity of tumor cells by immune cells. Compound 24 displays great pharmacokinetics (oral bioavailability of 22%) and significant in vivo antitumor activity in a CT26 mouse model. Flow cytometry and immunohistochemistry data indicated that compound 24 activates the immune activity in tumors. These results suggest that compound 24 is a promising small-molecule inhibitor against the PD-1/PD-L1 axis and merits further development.

Original languageEnglish (US)
Pages (from-to)7390-7403
Number of pages14
JournalJournal of Medicinal Chemistry
Volume64
Issue number11
DOIs
StatePublished - Jun 10 2021

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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