2. Academic Validation
  3. 4,6-Disubstituted-1H-Indazole-4-Amine derivatives with immune-chemotherapy effect and in vivo antitumor activity

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

  • Eur J Med Chem. 2022 Nov 5;241:114625. doi: 10.1016/j.ejmech.2022.114625.
Cui Huo 1,  Zongyuan Luo 1,  Xiangli Ning 2,  Xin Kang 3,  Qin Yan 1,  Yuying Guo 1,  Guobo Li 2,  Zhouyu Wang 1,  Yuzhi Li 4,  Shan Qian 5
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Engineering, College of Food and Bioengineering, Xihua University, Chengdu, 610039, China.
  • 2 Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China.
  • 3 State Key Laboratory of Southwestern Chinese Medicine Resources, Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu, 610091, China.
  • 4 State Key Laboratory of Southwestern Chinese Medicine Resources, Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu, 610091, China. Electronic address: liyuzhi5654@163.com.
  • 5 Department of Pharmaceutical Engineering, College of Food and Bioengineering, Xihua University, Chengdu, 610039, China. Electronic address: qians@mail.xhu.edu.cn.
PMID: 35952399 DOI: 10.1016/j.ejmech.2022.114625
Abstract

Tryptophan-2,3-dioxygenase (TDO) and indoleamine-2, 3-dioxygenase 1 (IDO1) are the important tumor immune checkpoints and TDO and IDO1 inhibition may present a potential approach to activate the T cell-mediated antitumor immune response during Cancer treatment. Herein, we designed and synthesized a series of nitro-aryl 1H-indazole derivatives. SARs analysis showed that the nitro-aryl at the C-4 position of 1H-indazole was beneficial for TDO inhibition and directly tumoricidal effect and the substituents at C-6 position of 1H-indazole significantly affected the activity and selectivity of IDO1/TDO. Among these derivatives, HT-28 and HT-30 demonstrated nanomolar potency and excellent selectivity against TDO with IC50 values of 0.62 μM and 0.17 μM respectively, and HT-37 showed the IDO1 and TDO dual-target inhibitory activity with IC50 values of 0.91 μM and 0.46 μM against IDO1 and TDO. Moreover, HT-28 showed the significant tumoricidal effect on six tumor cell lines, while HT-30 and HT-37 had almost no cytotoxic activity on these tumor cells. In the CT-26 allograft BALB/c mice, HT-28 had the significant in vivo antitumor activity at a lower dose. IHC staining assay indicated that HT-28 could reduce the expression of Foxp3 and enhance the expression of CD8 and TNF-α in tumor tissue. In summary, we developed a difunctional monomer with immune-chemotherapy effect to obtain the better in anti-tumor activity.

Keywords

Antitumor effects; Dual-target inhibitor; Immune chemotherapy; Indoleamine 2,3-dioxygenase 1 (IDO1); Tryptophan 2,3-dioxygenase (TDO).

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-151425
    99.07%, TDO抑制剂
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