Dual inhibitor targeting JAK/STAT and NF kappa B signal channels and application thereof

A dual inhibitor and signaling pathway technology, applied in medical preparations containing active ingredients, anti-inflammatory agents, non-central analgesics, etc., to achieve the effect of improving survival rate

Active Publication Date: 2021-07-09
OCEAN UNIV OF CHINA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

L971-0101 is a new type of diaromatic urea compound containing morpholine ring and quinoline ring. It comes from the skeleton compound collected by Tao Su. There is no report on the detailed mechanism of action of this compound.

Method used

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  • Dual inhibitor targeting JAK/STAT and NF kappa B signal channels and application thereof
  • Dual inhibitor targeting JAK/STAT and NF kappa B signal channels and application thereof
  • Dual inhibitor targeting JAK/STAT and NF kappa B signal channels and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] Example 1 Verification of the inhibitory effect of L971-0101 on JAK / STAT and NFκB signaling

[0050] Based on the screening of STAT3-driven luciferase reporter system, L971-0101 was obtained, and the firefly luciferase activity assay method and cell viability assay method (as above S1, S6 and S7 methods) were used to verify and evaluate the inhibition of L971-0101 on STAT3 signaling specificity.

[0051] Such as figure 1 As shown in A, it was found that L971-0101 had a concentration-dependent effect on luciferase activity (EC50=8.93μM), and L971-0101 had a significant inhibitory effect on STAT3 signaling. The effect of L971-0101 on STAT3 in prostate cancer cell line DU145 was detected in vitro Phosphorylation and effects of TNFα-induced IκB degradation in the cervical cancer cell line Hela.

[0052] Such as figure 1 As shown in B, L971-0101 can dose-dependently inhibit the constitutive activation of STAT3 in the concentration range of 0.94 μM, 1.88 μM, 3.75 μM, 7.5 μ...

Embodiment 2

[0053] Example 2 Verification of the effect of L971-0101 on inhibiting JAK / STAT and NFκB signaling in peritoneal macrophages

[0054] JAK / STAT and NFκB signaling are the regulatory centers that coordinate immune and inflammatory responses. In the classic JAK / STAT pathway, cytokines such as IL6 and interferon can induce the activation of STAT3 and STAT1 (as in methods S1, S2 and S3 above). Under IL6 stimulation, L971-0101 could dose-dependently inhibit the activation of STAT3 in mouse primary peritoneal macrophages in the concentration range of 2.5 μM, 5 μM, 7.5 μM, and 15 μM ( figure 2 A). L971-0101 also inhibited IFNβ-induced STAT1 phosphorylation in a dose-dependent manner in the concentration range of 2.5 μM, 5 μM, 7.5 μM, and 15 μM ( figure 2 B). It was further found that L971-0101 also inhibited the production of TNFα ( figure 2 C) and LPS ( figure 2 D) Induced phosphorylation of IKK.

Embodiment 3

[0055] Example 3 Verification that L971-0101 inhibits the downstream gene expression of JAK / STAT and NFκB signaling in peritoneal macrophages

[0056] Since LPS can sequentially activate JAK / STAT and NFκB signaling, the expression of their downstream genes was also detected (as in methods S1 and S4 above).

[0057] The results showed that 5 μM and 7.5 μM L971-0101 could inhibit the IL 6 induced by LPS stimulation at 3 h and 6 h ( image 3 A), IL 1β ( image 3 B) and CXCL1 ( image 3 D) expression, and inhibition of TNFα induced by 6h LPS stimulation ( image 3 C) Expression. The results showed that L971-0101 may play an anti-inflammatory role by inhibiting JAK / STAT and NFκB signaling and their downstream gene expression in peritoneal macrophages.

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Abstract

The invention provides a dual inhibitor targeting JAK / STAT and NF kappa B signal channels and an application thereof, and belongs to the technical field of biology. The invention provides a novel dual inhibitor L971-0101 capable of targeting JAK / STAT and NF kappa B signal channels, which has an inhibition effect on phosphorylation of STAT3 in a prostate cancer cell line DU145 and TNF alpha-induced I kappa B degradation in a cervical cancer cell line Hela, in addition, the dual inhibitor L971-0101 can relieve symptoms of LPS-induced sepsis shock mice in vivo, and effectively improves the survival rate of the mice, therefore, the product can be used as a potential inflammation inhibitor and has the potential of treating septicemia.

Description

technical field [0001] The invention belongs to the field of biotechnology, and in particular relates to a dual inhibitor targeting JAK / STAT and NFκB signaling pathways and application thereof. Background technique [0002] Inflammation is an immune response that occurs when the body encounters trauma, infection, tissue damage or harmful stimuli. The inflammatory process is controlled by various immune cells (such as neutrophils and macrophages) as well as most signaling pathways. A large number of proinflammatory cytokines such as interleukin 1 (IL1), IL6 and tumor necrosis factor α (TNFα) play important roles in JAK / STAT and NFκB signaling pathways. For example, in the inflammation caused by septic shock, NFκB, interferon regulatory factors 3 and 7 are rapidly activated after the recognition receptors are stimulated, resulting in the secretion of cytokines and chemokines (including IL6 and interferon), which in turn activate JAK / STAT signaling triggers a multitude of sig...

Claims

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Application Information

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IPC IPC(8): A61K31/5377A61P29/00A61P31/04
CPCA61K31/5377A61P29/00A61P31/04
Inventor 杨金波张心心宋巧玲赵晨阳
Owner OCEAN UNIV OF CHINA
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