4,6-Substituted-1H-Indazoles as potent IDO1/TDO dual inhibitors

Related Experiment Video

Updated: Jan 29, 2026

Author Spotlight: Advancing Therapeutics to Treat Vibriosis in Humans and Aquatic Organisms
03:29

Author Spotlight: Advancing Therapeutics to Treat Vibriosis in Humans and Aquatic Organisms

Published on: May 31, 2024

930

Lingling Yang1, Yang Chen1, Junlin He2

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

Bioorganic & Medicinal Chemistry
|February 19, 2019
PubMed

Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO) are constitutively overexpressed in many types of cancer cells and exert important immunosuppressive functions. In this article, a series of 4,6-substituted-1H-indazole derivatives were synthesized and evaluated the inhibitory activities against IDO1 and TDO, as well as their structure-activity relationships (SARs). Among these, compound 35 displayed the most IDO1 inhibitory potency with an IC50 value of 0.74 μM in an enzymatic assay and 1.37 μM in HeLa cells. Quantitative analysis of the Western blot results indicated that 35 significantly decreased the INFγ-induced IDO1 expression in a concentration-dependent manner. In addition, 35 showed promising TDO inhibition with an IC50 value of 2.93 μM in the enzymatic assay and 7.54 μM in A172 cells. Moreover, compound 35 exhibited in vivo antitumor activity in the CT26 xenograft model. These findings suggest that 1H-indazole derivative 35 is a potent IDO1/TDO dual inhibitor, and has the potential to be developed for IDO1/TDO-related cancer treatment.

Keywords:
1H-IndazolesAntitumor activityCancer immunotherapyDual inhibitorIndoleamine 2,3-dioxygenase 1 (IDO1)Tryptophan 2,3-dioxygenase (TDO)

More Related Videos

Synthesis and Evaluation of a Ruthenium-based Mitochondrial Calcium Uptake Inhibitor07:12

Synthesis and Evaluation of a Ruthenium-based Mitochondrial Calcium Uptake Inhibitor

Published on: October 26, 2017

8.2K
Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors08:45

Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors

Published on: July 17, 2020

6.6K

Related Concept Videos

Eukaryotic Transcription Inhibitors01:52

Eukaryotic Transcription Inhibitors

Certain biochemical processes, such as embryonic development and cell growth regulation, depend on the repression of specific genes. DNA binding proteins known as eukaryotic transcription inhibitors regulate the repression of gene expression in eukaryotes. The presence of these inhibitors at the required location and time in the cell is triggered by the presence of hormones and additional signals from other cells.
Eukaryotic transcription inhibitors usually contain two distinct domains, a...
11.0K
Trigonometric Substitution01:23

Trigonometric Substitution

Trigonometric substitution is a technique used to simplify integrals that contain square root expressions involving quadratic forms. It is particularly effective when the integrand includes terms resembling those found in standard geometric equations, such as circles or ellipses.Molniya satellites follow highly elliptical orbits, repeatedly sweeping out the same regions of space as they revolve around Earth. To estimate the area enclosed by such an orbit, the path is modeled as an ellipse...
54
Rationalizing Substitutions01:29

Rationalizing Substitutions

Integrals involving non-rational functions are often difficult to evaluate using standard techniques, especially when radicals appear in the integrand. Rationalizing substitution provides a systematic method for simplifying such integrals by converting them into rational forms that are easier to handle.Consider a rod whose linear mass density depends on a constant linear density, a characteristic length, and the distance from the left end of the rod. Determining the total mass requires...
57
Diazonium Group Substitution: –OH and –H01:19

Diazonium Group Substitution: –OH and –H

Nitrous acid, a weak acid, is prepared in situ via the reaction of sodium nitrite with a strong acid under cold conditions. This nitrous acid prepared in situ reacts with primary arylamines to form arenediazonium salts. Such reactions are known as diazotization reactions. As shown in Figure 1, the formation of arenediazonium salts begins with the decomposition of nitrous acid in an acidic solution to give nitrosonium ions.
3.4K
Evaluating Limits by Direct Substitution01:29

Evaluating Limits by Direct Substitution

In the analysis of functions that represent continuous physical phenomena, it is often necessary to determine the output value as the input approaches a specific point. When a combination of algebraic terms defines the function and exhibits no discontinuities or abrupt changes near the point of interest, the limit of the function can be evaluated directly. This process, known as direct substitution, involves replacing the variable in the expression with the value it approaches.Direct...
170
Stability of Substituted Cyclohexanes02:30

Stability of Substituted Cyclohexanes

This lesson discusses the stability of substituted cyclohexanes with a focus on energies of various conformers and the effect of 1,3-diaxial interactions.
The two chair conformations of cyclohexanes undergo rapid interconversion at room temperature. Both forms have identical energies and stabilities, each comprising equal amounts of the equilibrium mixture. Replacing a hydrogen atom with a functional group makes the two conformations energetically non-equivalent.
For example, in...
15.1K