2. Academic Validation
  3. 1-(3,4-Diaminophenyl)-1H-pyrrole-2-carboxylic acids as potent apo-IDO1 inhibitors exhibiting efficacy in syngeneic tumor mouse models

1-(3,4-Diaminophenyl)-1H-pyrrole-2-carboxylic acids as potent apo-IDO1 inhibitors exhibiting efficacy in syngeneic tumor mouse models

  • Eur J Med Chem. 2026 Jan 5:301:118222. doi: 10.1016/j.ejmech.2025.118222.
Yi Zou 1,  Shushan Ge 2,  Haiqing Zhong 3,  Yingbo Zheng 4,  Xuewei Ma 4,  Wenbin Liu 4,  Fang Wang 4,  Wenjie Guo 3,  Wen Liu 5,  Qiang Xu 6,  Yisheng Lai 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, PR China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, PR China. Electronic address: zouyi@cpu.edu.cn.
  • 2 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, PR China; Department of Nuclear Medicine, The First Affiliated Hospital of Soochow University, Suzhou, 215006, PR China.
  • 3 State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210093, PR China.
  • 4 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, PR China.
  • 5 State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210093, PR China. Electronic address: liuwen@nju.edu.cn.
  • 6 State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210093, PR China. Electronic address: molpharm@163.com.
  • 7 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: yslai@cpu.edu.cn.
PMID: 41061297 DOI: 10.1016/j.ejmech.2025.118222
Abstract

Indolamine 2,3-dioxygenase 1 (IDO1)-mediated kynurenine pathway has been identified as an important immune escape mechanism in Cancer, and pharmacological inhibition of IDO1 is regarded as a potential strategy for Cancer treatment. Herein, we describe the identification of novel 1H-pyrrole-2-carboxylic acid-based IDO1 inhibitors targeting its apo form with picomolar potency in the HeLa cell-based assay. Among them, compound 45 showed the strongest inhibitory activity against IDO1 with an IC50 value of 10 pM. Notably, oral administration of 45 at 10 mg/kg significantly suppressed tumor growth by activating antitumor immunity without significant toxicity in a CT26 syngeneic mouse model. Furthermore, the tumor burden could similarly be decreased in an LLC syngeneic mouse model treated with 45, indicating the potential of 45 for the treatment of distinct tumor types. Collectively, these data suggest that compound 45 may be used as a promising lead compound for further investigation.

Keywords

Apo-IDO1 inhibitor; Immunotherapy; Molecular docking; Molecular dynamic simulation; T cell.

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