Discovery of (E)-2-cyano-N-(2,3-dihydrobenzo[b][1,4] dioxin-6-yl)-3-(1H-indol-3-yl)acrylamide as a novel TDO inhibitor for cancer treatment

  • Bioorg Chem. 2025 Jul 1:161:108555. doi: 10.1016/j.bioorg.2025.108555.
Xiang Wang  1 ,  Xiaoshuang Wang  2 ,  Xiaoxue Wang  2 ,  Kejia Xu  2 ,  Jie Long  2 ,  Yanan Chen  2 ,  Yanhua Liu  2 ,  Haiying Niu  3 ,  Beilei Zeng  4 ,  Yan Fan  5
Affiliations
  • 1. Xingzhi College, Zhejiang Normal University, Lanxi, 321004, China.
  • 2. School of Medicine, Nankai University, 94 Weijin Road, Tianjin 300071, China.
  • 3. Department of Gynecology, Tianjin First Central Hospital, Tianjin, China.. Electronic address: [email protected].
  • 4. Department of Oncology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China.. Electronic address: [email protected].
  • 5. School of Medicine, Nankai University, 94 Weijin Road, Tianjin 300071, China. Electronic address: [email protected].
PMID: 40359840 DOI: 10.1016/j.bioorg.2025.108555
Abstract

Tryptophan 2,3- oxygenase (TDO), an immune-suppressing enzyme, catalyzes the catabolism of tryptophan to N-formylkynurenine. Overexpression of TDO in multiple malignancies associates with immune evasion mechanisms. Therefore, we aimed to discover novel inhibitors targeting TDO as a potential strategy for Cancer treatment. In this study, we designed and synthesized a series of (E)-2-cyano-3-(1H-indol-3-yl) acrylamide derivatives. A lead compound, 5c, was identified and exhibited inhibitory activity against TDO, with an IC50 value of 1.25 ± 0.04 μM. 5c demonstrated significant tumor growth suppression with a favorable safety profile in Hepa1-6 hepatocellular carcinoma allograft model. Notably, 5c synergized with the PD-1/PD-L1 inhibitor BMS-202, both in vitro and in vivo. These findings suggested compound 5c could serve as a promising candidate for targeting TDO to address tumor immune tolerance in Cancer therapy.

Keywords
Immunotherapy; PD-1/PD-L1; TDO; cancer.
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