Synthesis and Evaluation of Biphenyl-1,2,3-Triazol-Benzonitrile Derivatives as PD-1/PD-L1 Inhibitors

Suresh Narva; Xuqiong Xiong; Xudong Ma; Yoshimasa Tanaka; Yanling Wu; Wen Zhang

doi:10.1021/acsomega.0c02916

Synthesis and Evaluation of Biphenyl-1,2,3-Triazol-Benzonitrile Derivatives as PD-1/PD-L1 Inhibitors

ACS Omega. 2020 Aug 14;5(33):21181-21190. doi: 10.1021/acsomega.0c02916. eCollection 2020 Aug 25.

Authors

Suresh Narva^{1

2}, Xuqiong Xiong^{1

2}, Xudong Ma^{1

2}, Yoshimasa Tanaka³, Yanling Wu⁴, Wen Zhang^{1

2}

Affiliations

¹ Laboratory of Chemical Biology and Molecular Drug Design, College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, China.
² Institute of Drug Development & Chemical Biology, Zhejiang University of Technology, Hangzhou 310014, China.
³ Center for Medical Innovation, Nagasaki University, 1-7-1 Sakamoto, Nagasaki 852-8588, Japan.
⁴ Laboratory of Molecular Immunology, Virus Inspection Department, Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou 310051, China.

Abstract

In this study, we designed and synthesized a series of 3-(4-((5-((2-methylbiphenyl-3-yl) methoxy)-2-(piperazin-1-ylmethyl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)benzonitrile derivatives and examined the effect of the compounds on the interaction between PD-1 and PD-L1. Among the newly synthesized compounds, compound 7 exhibited the most potent inhibitory activity for PD-1/PD-L1 binding, with an IC₅₀ value being 8.52 μM, through homogeneous time-resolved fluorescence (HTRF) assay. Docking studies indicated that compound 7 can very well interact with PD-L1 dimerization like BMS-202 as a positive control, consistent with the results of the HTRF assay. Compound 7 is thus a promising candidate for further optimization as an inhibitor of the PD-1/PD-L1 signaling pathway.