Discovery of benzo[d]isothiazole derivatives as novel scaffold inhibitors targeting the programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) interaction through "ring fusion" strategy

Yinli Gao; Hanxun Wang; Lanlan Shen; Hanqing Xu; Minghui Deng; Maosheng Cheng; Jian Wang

doi:10.1016/j.bioorg.2022.105769

Discovery of benzo[d]isothiazole derivatives as novel scaffold inhibitors targeting the programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) interaction through "ring fusion" strategy

Bioorg Chem. 2022 Jun:123:105769. doi: 10.1016/j.bioorg.2022.105769. Epub 2022 Apr 4.

Authors

Yinli Gao¹, Hanxun Wang¹, Lanlan Shen¹, Hanqing Xu¹, Minghui Deng¹, Maosheng Cheng², Jian Wang³

Affiliations

¹ School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning, P. R. China; Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning, P. R. China; Key Laboratory of Intelligent Drug Design and New Drug Discovery of Liaoning Province, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning, P. R. China.
² School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning, P. R. China; Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning, P. R. China; Key Laboratory of Intelligent Drug Design and New Drug Discovery of Liaoning Province, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning, P. R. China. Electronic address: mscheng@syphu.edu.cn.
³ School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning, P. R. China; Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning, P. R. China; Key Laboratory of Intelligent Drug Design and New Drug Discovery of Liaoning Province, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning, P. R. China. Electronic address: jianwang@syphu.edu.cn.

PMID: 35405572
DOI: 10.1016/j.bioorg.2022.105769

Abstract

The inhibition of programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) interaction by monoclonal antibodies (mAbs) has achieved promising outcomes in cancer immunotherapy. Due to the inherent deficiencies of mAbs drugs, such as high cost of treatment, immunogenicity, poor pharmacokinetics and penetration of solid tumors, researchers are encouraged to develop small molecule inhibitors, to overcome mAbs drugs' deficiencies and change the situation where small molecule drugs are not available on the market. Herein, we reported a series of benzo[d]isothiazole derivatives targeting the PD-1/PD-L1 interaction through "ring fusion" strategy using BMS-202 as a starting point. Among them, compound D7 exhibited the best inhibitory activity with an IC₅₀ value of 5.7 nM by homogeneous time-resolved fluorescence (HTRF) binding assay. In immunotoxicity analysis, D7 showed low cytotoxicity to Jurkat T cells in CCK-8 assay compared to BMS-202. The binding mode between D7 and PD-L1 protein was explored by molecular docking and molecular dynamics (MD) simulations, which revealed crucial chemical groups, such as biphenyl group interacting with Ile54_A, Tyr56_A, Met115_A, Ala121_A, Ile54_B, Met115_B, Ala121_B and Tyr123_B by hydrophobic interactions, bromobenzene moiety forming π-π stacking interaction with Tyr56_B, as well as l-serine moiety forming hydrogen bond (H-bond) and salt bridge interactions with Asp122_A and Lys124_A. Furthermore, molecular modeling studies showed that D7 is likely to bind to the FA8 (fatty acid 8) binding site of human serum albumin (HSA). Taken together, D7 significantly inhibits the PD-1/PD-L1 interaction with low cytotoxicity, indicating that D7 is a promising starting point for further drug development in cancer immunotherapy.

Keywords: Benzo[d]isothiazole derivatives; Molecular docking; Molecular dynamics simulations; PD-1/PD-L1 interaction; Tumor immunotherapy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Apoptosis
B7-H1 Antigen*
Humans
Ligands
Molecular Docking Simulation
Molecular Dynamics Simulation
Neoplasms*
Programmed Cell Death 1 Receptor / chemistry
Programmed Cell Death 1 Receptor / metabolism
Structure-Activity Relationship

Substances

B7-H1 Antigen
Ligands
Programmed Cell Death 1 Receptor