2. Academic Validation
  3. Discovery of the programmed cell death-1/programmed cell death-ligand 1 interaction inhibitors bearing an indoline scaffold

Discovery of the programmed cell death-1/programmed cell death-ligand 1 interaction inhibitors bearing an indoline scaffold

  • Eur J Med Chem. 2020 Jan 15;186:111856. doi: 10.1016/j.ejmech.2019.111856.
Mingze Qin 1,  Qi Cao 2,  Xia Wu 2,  Chunyang Liu 2,  Shuaishuai Zheng 2,  Hongbo Xie 3,  Ye Tian 2,  Jun Xie 4,  Yanfang Zhao 2,  Yunlei Hou 2,  Xian Zhang 2,  Boxuan Xu 2,  Haotian Zhang 5,  Xiaobo Wang 6
Affiliations

Affiliations

  • 1 Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, PR China; Chinese People's Liberation Army Logistics Support Force No. 967 Hospital, Dalian, 116021, PR China. Electronic address: qinmingze001@126.com.
  • 2 Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, PR China.
  • 3 College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150086, PR China.
  • 4 Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, 110016, PR China.
  • 5 Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, 110016, PR China. Electronic address: zhanghaotian2087@163.com.
  • 6 Chinese People's Liberation Army Logistics Support Force No. 967 Hospital, Dalian, 116021, PR China. Electronic address: wxbbenson0653@sina.com.
PMID: 31734021 DOI: 10.1016/j.ejmech.2019.111856
Abstract

Inhibiting the programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) pathway is an attractive strategy for tumor immunotherapy. Here, a novel series of indoline-containing compounds were developed, among which, A13 was identified as the most promising PD-1/PD-L1 pathway inhibitor. At the biochemical level, A13 demonstrated strong inhibition of the PD-1/PD-L1 interaction, with an IC50 of 132.8 nM. Notably, it exhibited outstanding immunoregulatory activity, and significantly elevated interferon-γ secretion in a Hep3B/OS-8/hPD-L1 and CD3 T cell co-culture model, without significant toxic effect. Therefore, A13 could be employed as a suitable lead compound for further design of non-peptide inhibitors targeting the PD-1/PD-L1 interaction. In addition, the preliminary structure-activity relationships of these new indoline compounds were investigated in this study, providing valuable information for future drug development.

Keywords

IFN-γ secretion; Low toxicity; PD-1/PD-L1 interaction inhibitor; Tumor immunotherapy.

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