Discovery of 4-phenylindolines containing a (5-cyanopyridin-3-yl)methoxy moiety as potent inhibitors of the PD-1/PD-L1 interaction

  • Bioorg Med Chem Lett. 2022 May 1;63:128647. doi: 10.1016/j.bmcl.2022.128647.
Yangyang Meng  1 ,  Cuiping Chu  1 ,  Xinyu Niu  1 ,  Liuyang Cheng  1 ,  Di Wu  1 ,  Lei Liu  1 ,  Shaopeng Zhang  1 ,  Tianqi Li  1 ,  Yunlei Hou  1 ,  Yajing Liu  1 ,  Mingze Qin  2
Affiliations
  • 1. Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
  • 2. Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China. Electronic address: [email protected].
PMID: 35231577 DOI: 10.1016/j.bmcl.2022.128647
Abstract

With the great success of anti-programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) monoclonal antibodies in clinical applications, blocking the PD-1/PD-L1 pathway has become the most compelling strategy in the field of tumor immunotherapy. In this study, a novel series of 4-phenylindolines containing a (5-cyanopyridin-3-yl)methoxy moiety were developed, and their structure-activity relationships were preliminarily discussed. Among them, compounds M17 and M23 exhibited the most potent ability to disrupt the PD-1/PD-L1 interaction, demonstrating IC50 values of 60.1 nM and 53.2 nM, respectively. The binding mode of M23 was further explored by molecular docking analysis with dimeric PD-L1. Therefore, M17 and M23 are promising lead compounds for developing potent inhibitors of the PD-1/PD-L1 axis.

Keywords
4-phenylindoline; PD-1/PD-L1 inhibitors; Tumor immunotherapy.
Products