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4,6-Disubstituted-1H-Indazole-4-Amine derivatives with immune-chemotherapy effect and in vivo antitumor activity

Cui Huo1, Zongyuan Luo1, Xiangli Ning2

  • 1Department of Pharmaceutical Engineering, College of Food and Bioengineering, Xihua University, Chengdu, 610039, China.

European Journal of Medicinal Chemistry
|August 11, 2022
PubMed

Insights

Researchers developed novel nitro-aryl 1H-indazole derivatives targeting tumor immune checkpoints. Compound HT-28 showed significant antitumor activity and modulated immune responses in vivo, offering a potential immune-chemotherapy approach.

Area of Science:

  • Medicinal Chemistry
  • Cancer Immunology
  • Drug Discovery

Background:

  • Tryptophan-2,3-dioxygenase (TDO) and indoleamine-2,3-dioxygenase 1 (IDO1) are key tumor immune checkpoints.
  • Inhibiting TDO and IDO1 can potentially activate T cell-mediated antitumor immune responses.

Purpose of the Study:

  • To design and synthesize novel nitro-aryl 1H-indazole derivatives as potential cancer therapeutics.
  • To evaluate the inhibitory activity and selectivity of these derivatives against TDO and IDO1.
  • To assess the in vitro and in vivo antitumor efficacy and immune-modulating effects of promising compounds.

Main Methods:

  • Synthesis of a series of nitro-aryl 1H-indazole derivatives.
  • Structure-Activity Relationship (SAR) analysis for TDO and IDO1 inhibition.
  • In vitro enzyme inhibition assays (IC50 determination).
  • In vitro tumoricidal effect assays on multiple cancer cell lines.
  • In vivo antitumor activity assessment in a CT-26 allograft mouse model.
  • Immunohistochemistry (IHC) staining to analyze immune cell markers (Foxp3, CD8, TNF-α) in tumor tissues.

Main Results:

  • SAR analysis indicated the importance of the C-4 nitro-aryl group for TDO inhibition and tumoricidal effects, and C-6 substituents for IDO1/TDO selectivity.
  • Compounds HT-28 and HT-30 exhibited nanomolar potency and high selectivity for TDO inhibition.
  • HT-37 displayed dual inhibitory activity against both IDO1 and TDO.
  • HT-28 demonstrated significant tumoricidal effects across six tumor cell lines and potent in vivo antitumor activity in mice.
  • HT-28 treatment reduced Foxp3 expression and increased CD8 and TNF-α expression in tumor tissues, indicating immune modulation.

Conclusions:

  • Novel nitro-aryl 1H-indazole derivatives were successfully designed and synthesized.
  • HT-28 emerged as a promising candidate with potent TDO inhibitory and direct tumoricidal activity, coupled with significant in vivo antitumor efficacy and immune-modulating properties.
  • These findings support the development of TDO inhibitors as a difunctional immune-chemotherapy strategy for cancer treatment.
Keywords:
Antitumor effectsDual-target inhibitorImmune chemotherapyIndoleamine 2,3-dioxygenase 1 (IDO1)Tryptophan 2,3-dioxygenase (TDO)

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