具有苯并[d]异噻唑骨架的程序性细胞死亡-1/程序性细胞死亡配体 1 相互作用抑制剂的设计、合成及构效关系研究。
Design, synthesis, and structure-activity relationship of programmed cell death-1/programmed cell death-ligand 1 interaction inhibitors bearing a benzo[d]isothiazole scaffold.
机构信息
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.
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.
出版信息
Eur J Med Chem. 2021 May 5;217:113377. doi: 10.1016/j.ejmech.2021.113377. Epub 2021 Mar 15.
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 IC 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 EC value of 5.6 μM CH20 could have better potency in restoring the activity of effector cells, as the maximal luminescence values (RLU) 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.
阻断程序性细胞死亡蛋白-1（PD-1）/程序性细胞死亡配体 1（PD-L1）通路是免疫治疗的一种有吸引力的策略。开发了一系列含有苯并[d]异噻唑骨架的新型化合物，其中 CH20 表现出有希望的活性，IC 值为 8.5 nM。进一步的基于细胞的 PD-1/PD-L1 阻断生物测定表明，CH20 可以在细胞水平抑制 PD-1/PD-L1 相互作用，EC 值为 5.6 μM。CH20 可能在恢复效应细胞活性方面具有更好的效力，因为 CH20 的最大发光值（RLU）与 PD-L1 mAbs 的相当。CH20 与 PD-L1 二聚体复合物（PDB ID：6R3K）的对接分析证实，CH20 是开发 PD-1/PD-L1 相互作用抑制剂的有前途的先导化合物。本文研究了初步的构效关系，旨在为未来的药物开发提供参考。
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