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Application of reagent for inhibiting activity of protein kinase CLK in preparation of medicine for treating or improving esophageal squamous cell carcinoma

A technology of inhibiting proteins and inhibitors, which is applied in the field of tumor detection and can solve the problems of lack of targeted therapy

Active Publication Date: 2021-08-10
CANCER INST & HOSPITAL CHINESE ACADEMY OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Most patients, especially those with poor prognosis and advanced esophageal cancer, still lack effective targeted therapy

Method used

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  • Application of reagent for inhibiting activity of protein kinase CLK in preparation of medicine for treating or improving esophageal squamous cell carcinoma
  • Application of reagent for inhibiting activity of protein kinase CLK in preparation of medicine for treating or improving esophageal squamous cell carcinoma
  • Application of reagent for inhibiting activity of protein kinase CLK in preparation of medicine for treating or improving esophageal squamous cell carcinoma

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] In this example, 94 cases of ESCC tumor samples were analyzed by mass spectrometry for proteome and phosphorylation modification group. These ESCC can be divided into three subtypes according to proteomic characteristics ( figure 1 Middle a).

[0049] Among them, subtype III ( figure 1 Middle b) is characterized by elevated proteome and phosphoproteome levels in the spliceosome signaling pathway ( figure 1 Middle a).

[0050] Detect the expression of CD2BP2 and WBP11 proteins in different subtypes of tumors, see the results figure 2 . Depend on figure 2 It can be seen that the expression of CD2BP2 and WBP11 proteins in III subtype tumors was significantly up-regulated compared with other subtypes.

[0051] At the same time, functional experiments showed that these two proteins played an important role in the proliferation of esophageal cancer cells. In vitro CCK8 experiments showed that both CD2BP2 and WBP11 knockdown significantly inhibited the growth of ESCC c...

Embodiment 2

[0053] Validation of the effects of CD2BP2 and WBP11 on the protein kinase CLK.

[0054] Analysis of the pairing relationship between phosphatase and kinase (PRA) showed that the phosphorylated proteins regulated by the two negative regulators of PP1 (CD2BP2 and WBP11) mainly corresponded to the enzyme substrate of protein kinase CLK ( Figure 4 Middle a).

[0055] Therefore, CD2BP2 and WBP11 can be regarded as enhancer proteins of CLK kinases. At the same time, the results showed that CD2BP2 and WBP11 proteins had the highest expression levels in the III subtype of ESCC, and it was consistent that the CLK kinase activity was also the highest in the III subtype ( Figure 4 Middle b).

Embodiment 3

[0057] To verify the effect of CLK kinase inhibitors on ESCC.

[0058] In this example, the CLK kinase-specific inhibitor TG003 was used to act on three ESCC patient-derived tumor xenograft models (PDX models), and the effect of the inhibitor TG003 on tumors was tested. See the results in Figure 5 .

[0059] Depend on Figure 5 From a to c, it can be seen that TG003, a specific inhibitor of CLK kinase, has the best inhibitory effect in PDX#2, and also has a certain inhibitory effect in PDX#1 model.

[0060] In PDX model II, where the inhibitory effect of CLK kinase-specific inhibitor TG003 was the most significant, in model II, the expression levels of CLK kinase enhancer proteins CD2BP2 and WBP11 were the highest, while in the other two PDX models, the protein expression levels of CD2BP2 and WBP11 generally( Figure 5 middle d).

[0061] In summary, the present invention provides an application of a reagent that inhibits the activity of protein kinase CLK in the preparat...

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Abstract

The invention discloses application of a reagent for inhibiting the activity of protein kinase CLK in preparation of a medicine for treating or improving esophageal squamous cell carcinoma, and relates to the technical field of tumor detection. Analysis is conducted on an esophageal squamous cell carcinoma tumor sample, it is found that the activity of the protein kinase CLK in an ESCC patient is abnormally increased, and by inhibiting the activity of the CLK, the purpose of effectively treating or improving ESCC can be achieved, and a new way is provided for treatment and mechanism research of ESCC.

Description

technical field [0001] The invention relates to the technical field of tumor detection, in particular to the application of a reagent for inhibiting the activity of protein kinase CLK in the preparation of medicines for treating or improving esophageal squamous cell carcinoma. Background technique [0002] Esophageal squamous cell carcinoma (ESCC) is a common malignant tumor. Because there is still no effective treatment for esophageal cancer, its mortality rate remains high. ESCC is affected by environmental factors (drinking and smoking, etc.) and genetic factors, both of which lead to tumorigenesis by altering the proteomics, post-translational modifications (PTMs) and metabolic characteristics of the esophageal epithelium. [0003] Recently, multiple research centers have discovered multiple new driver gene mutations that are closely related to the development of ESCC through large-scale whole-genome sequencing of ESCC. However, the underlying mechanism of ESCC develop...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/00A61P35/00G01N33/68
CPCA61K45/00A61P35/00G01N33/6875G01N33/68
Inventor 李义刘芝华魏子超
Owner CANCER INST & HOSPITAL CHINESE ACADEMY OF MEDICAL SCI
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