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

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.
Hao Chen 1,  Ke Wang 2,  Yang Yang 2,  Xupeng Huang 2,  Xinyan Dai 2,  Zhiqiang Feng 3
Affiliations

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 (RLUmax) 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.

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