Design, synthesis, and structure-activity relationship of programmed cell death-1/programmed cell death-ligand 1 interaction inhibitors bearing a benzo[d]isothiazole scaffold

Hao Chen; Ke Wang; Yang Yang; Xupeng Huang; Xinyan Dai; Zhiqiang Feng

doi:10.1016/j.ejmech.2021.113377

Design, synthesis, and structure-activity relationship of programmed cell death-1/programmed cell death-ligand 1 interaction inhibitors bearing a benzo[d]isothiazole scaffold

Eur J Med Chem. 2021 May 5:217:113377. doi: 10.1016/j.ejmech.2021.113377. Epub 2021 Mar 15.

Authors

Hao Chen¹, Ke Wang², Yang Yang², Xupeng Huang², Xinyan Dai², Zhiqiang Feng³

Affiliations

¹ Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China; Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China. Electronic address: chenhao@imm.ac.cn.
² Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China; Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China.
³ Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China; Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China. Electronic address: fengzhq@imm.ac.cn.

PMID: 33770574
DOI: 10.1016/j.ejmech.2021.113377

Abstract

Blockade of the programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) pathway is an attractive strategy for immunotherapy. A novel series of compounds bearing a benzo[d]isothiazole scaffold were developed, among which CH20 exhibited promising activity, with an IC₅₀ value of 8.5 nM. Further cell-based PD-1/PD-L1 blockade bioassays indicated that CH20 can inhibit the PD-1/PD-L1 interaction at the cellular level, with an EC₅₀ value of 5.6 μM CH20 could have better potency in restoring the activity of effector cells, as the maximal luminescence values (RLU_max) of CH20 were equivalent to those of PD-L1 mAbs. The docking analysis of CH20 with the PD-L1 dimer complex (PDB ID: 6R3K) confirmed that CH20 is a promising lead compound for the development of inhibitors of the PD-1/PD-L1 interaction. The preliminary structure-activity relationship was investigated in this paper, with the aim of future drug development.

Keywords: Immunotherapy; PD-1/PD-L1 interaction inhibitors; benzo[d]isothiazole scaffold.

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
B7-H1 Antigen / antagonists & inhibitors*
B7-H1 Antigen / chemistry
Cell Line
Cell Proliferation / drug effects
Cell Survival / drug effects
Cricetulus
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Humans
Immune Checkpoint Inhibitors / chemical synthesis
Immune Checkpoint Inhibitors / chemistry
Immune Checkpoint Inhibitors / pharmacology*
Molecular Docking Simulation
Molecular Structure
Programmed Cell Death 1 Receptor / antagonists & inhibitors*
Programmed Cell Death 1 Receptor / chemistry
Structure-Activity Relationship
Thiazoles / chemical synthesis
Thiazoles / chemistry
Thiazoles / pharmacology*

Substances

Antineoplastic Agents
B7-H1 Antigen
CD274 protein, human
Immune Checkpoint Inhibitors
PDCD1 protein, human
Programmed Cell Death 1 Receptor
Thiazoles