2. Academic Validation
  3. Discovery of novel hydroxyamidine based indoleamine 2,3-dioxygenase 1 (IDO1) and thioredoxin reductase 1 (TrxR1) dual inhibitors

Discovery of novel hydroxyamidine based indoleamine 2,3-dioxygenase 1 (IDO1) and thioredoxin reductase 1 (TrxR1) dual inhibitors

  • Eur J Med Chem. 2023 Jan 5;245(Pt 1):114860. doi: 10.1016/j.ejmech.2022.114860.
Ji Zhou 1,  Li-Zhen Yu 2,  Ya-Li Fan 3,  Ci-Hao Guo 3,  Xiao-Mei Lv 3,  Zhi-Yin Zhou 3,  Hui-Dan Huang 3,  Dong-Dong Miao 3,  Sheng-Peng Zhang 3,  Xin-Yu Li 4,  Ping-Ping Zhao 4,  Xiao-Ping Liu 5,  Wei-Hua Hu 6,  Chao Zhang 7
Affiliations

Affiliations

  • 1 Center for Reproductive Medicine, The First Affiliated Hospital of Wannan Medical College, Wuhu, Anhui, 241000, PR China; Center of Drug Screening and Evaluation, Wannan Medical College, Wuhu, Anhui, 241000, PR China.
  • 2 School of Pharmacy, Wannan Medical College, Wuhu, Anhui, 241000, PR China.
  • 3 Center of Drug Screening and Evaluation, Wannan Medical College, Wuhu, Anhui, 241000, PR China.
  • 4 Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, 210009, PR China.
  • 5 Center of Drug Screening and Evaluation, Wannan Medical College, Wuhu, Anhui, 241000, PR China. Electronic address: liuxiaoping@wnmc.edu.cn.
  • 6 Center for Reproductive Medicine, The First Affiliated Hospital of Wannan Medical College, Wuhu, Anhui, 241000, PR China. Electronic address: weihuahu@126.com.
  • 7 Center of Drug Screening and Evaluation, Wannan Medical College, Wuhu, Anhui, 241000, PR China. Electronic address: zhangchao@wnmc.edu.cn.
PMID: 36370550 DOI: 10.1016/j.ejmech.2022.114860
Abstract

In order to take advantage of both immunotherapeutic and metabolic antitumor agents, novel dual indoleamine 2,3- dioxygenase 1 (IDO1) and thioredoxin reductase 1 (TrxR1) inhibitors were designed. Thioredoxin reductase 1 (TrxR1) is a main ROS modulator within CRC cells. Indoleamine 2,3-dioxygenase (IDO1) is crucial controller for tryptophan (Trp) metabolism that is also important for CRC immunotherapy. Herein, ten compounds 12a-j containing hydroxyamidine scaffold were designed, synthesized and evaluated for inhibitory activities against IDO1/TrxR1 Enzyme and CRC cells. Among these compounds, the most active compound 12d (ZC0109) showed excellent and balanced activity against both IDO1 (IC50 = 0.05 μM) and TrxR1 (IC50 = 3.00 ± 0.25 μM) were selected for further evaluation. Compound ZC0109 exhibited good dual inhibition against IDO1 and TrxR1 both in vitro and in vivo. Further mechanistic studies reveal that, through IDO1 and TrxR1 inhibition by ZC0109 treatment, accumulated ROS effectively induced Apoptosis and G1/S cell cycle arrest in Cancer cells. In vivo evaluation demonstrated excellent anti-tumor effect of ZC0109 with the notable ability of promoting ROS-induced Apoptosis, reducing kynurenine level in plasma and restoring anti-tumor immune response. Thus, ZC0109 represents a potential CRC therapy agent for further development.

Keywords

Antitumor; Dual inhibitor; IDO1; TrxR1; Tumor microenvironment.

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