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

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

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.

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