TY - JOUR
T1 - Novel Biphenyl Pyridines as Potent Small-Molecule Inhibitors Targeting the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 Interaction
AU - Wang, Tianyu
AU - Cai, Shi
AU - Wang, Mingming
AU - Zhang, Wanheng
AU - Zhang, Kuojun
AU - Chen, Dong
AU - Li, Zheng
AU - Jiang, Sheng
N1 - Funding Information:
This work was supported by the National Natural Science Foundation of China (81773559, 21807114, and 82161138005), the Double First-Class University Project (CPU2018GY03).
Publisher Copyright:
© 2021 American Chemical Society.
PY - 2021/6/10
Y1 - 2021/6/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85108021485&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85108021485&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.1c00010
DO - 10.1021/acs.jmedchem.1c00010
M3 - Article
C2 - 34056906
AN - SCOPUS:85108021485
SN - 0022-2623
VL - 64
SP - 7390
EP - 7403
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 11
ER -