CN113230405A - Application of agent for inhibiting activity of protein kinase CLK in preparation of medicine for treating or improving esophageal squamous cell carcinoma - Google Patents
Application of agent for inhibiting activity of protein kinase CLK in preparation of medicine for treating or improving esophageal squamous cell carcinoma Download PDFInfo
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- CN113230405A CN113230405A CN202110500549.7A CN202110500549A CN113230405A CN 113230405 A CN113230405 A CN 113230405A CN 202110500549 A CN202110500549 A CN 202110500549A CN 113230405 A CN113230405 A CN 113230405A
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Abstract
The invention discloses an application of a reagent for inhibiting 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.
Description
Technical Field
The invention relates to the technical field of tumor detection, in particular to application of a reagent for inhibiting activity of protein kinase CLK in preparation of a medicine for treating or improving esophageal squamous cell carcinoma.
Background
Esophageal Squamous Cell Carcinoma (ESCC) is a common malignancy. Because the esophagus cancer still lacks an effective treatment means at present, the death rate is high. ESCC is influenced by environmental factors (drinking, smoking, etc.) and genetic factors, both of which contribute to tumorigenesis by altering proteomics, post-translational modifications (PTMs), and metabolic characteristics of the esophageal epithelium.
Recently, a number of research centers have discovered a number of new driver mutations that are closely related to the development of ESCC by large-scale whole genome sequencing of ESCC. However, the underlying mechanisms of ESCC development are still unclear and a comprehensive protein mass spectrometry analysis of ESCC is essential to understand its underlying mechanisms, improve prognosis and guide treatment methods.
To date, treatment of ESCC patients has mainly included endoscopic therapy, surgery, chemotherapy, and radiation therapy (Ohashi et al, 2015). Most patients, especially those with poor prognosis and advanced esophageal cancer, still lack effective targeted therapy.
In view of this, the invention is particularly proposed.
Disclosure of Invention
The invention aims to provide application of an agent for inhibiting activity of protein kinase CLK in preparation of a medicine for treating or improving esophageal squamous cell carcinoma.
The invention is realized by the following steps:
in a first aspect, embodiments of the present invention provide the use of an agent that inhibits the activity of protein kinase CLK in the manufacture of a medicament for the treatment or amelioration of esophageal squamous cell carcinoma.
In a second aspect, the embodiments of the present invention provide the use of an inhibitor of CD2BP2 in the manufacture of an agent for inhibiting the activity of protein kinase CLK.
In a third aspect, embodiments of the present invention provide the use of a WBP11 inhibitor in the preparation of an agent for inhibiting protein kinase CLK activity.
In a fourth aspect, embodiments of the present invention provide the use of an inhibitor of CD2BP2 in the manufacture of a medicament for the treatment or amelioration of esophageal squamous cell carcinoma.
In a fifth aspect, embodiments of the present invention provide the use of an inhibitor of WBP11 in the manufacture of a medicament for the treatment or amelioration of esophageal squamous cell carcinoma.
In a sixth aspect, embodiments of the present invention provide use of an agent for detecting the expression level of a gene of interest selected from at least one of CD2BP2 and WBP11 in the preparation of an agent for detecting esophageal squamous cell carcinoma.
In a seventh aspect, embodiments of the present invention provide use of an agent for detecting the expression level of a gene of interest selected from at least one of CD2BP2 and WBP11 in screening a medicament for treating or ameliorating esophageal squamous cell carcinoma; such use is not directly aimed at the diagnosis or treatment of disease.
The invention has the following beneficial effects:
according to the invention, by analyzing an ESCC (esophageal squamous cell carcinoma) tumor sample, the abnormal increase of the activity of protein kinase CLK in an ESCC tumor tissue is found, and by inhibiting the activity of the protein kinase CLK, the aim of effectively treating or improving ESCC can be achieved, so that a new way is provided for the treatment and mechanism research of ESCC.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings needed to be used in the embodiments will be briefly described below, it should be understood that the following drawings only illustrate some embodiments of the present invention and therefore should not be considered as limiting the scope, and for those skilled in the art, other related drawings can be obtained according to the drawings without inventive efforts.
FIG. 1 is a heatmap of the protein molecular typing of ESCC tumor specimens in example 1; among them, a was 94 cases of ESCC tumor tissue and 3 subtypes were finally determined by consistent cluster analysis (Consensus clustering analysis) on proteome data: type I, type II and type III, the major functions associated with the protein clusters of the different subtypes are labeled on the left side of heatmap; b is Kaplan-Meier curve analysis of disease-free survival (DFS) of different ESCC subtypes;
in FIG. 2, a is the expression of WBP11 protein in paraneoplastic control tissues and different ESCC subtypes; b is the expression of CD2BP2 protein in a paracancer control tissue and different ESCC subtypes;
in FIG. 3, a is the effect of knocking down WBP11 on the growth rate of esophageal cancer cells (KYSE30& KYSE 150); b is the effect of knocking down CD2BP2 on the growth rate of esophageal cancer cells (KYSE30& KYSE 150);
FIGS. 4 a-b are the first 20 kinases in the Paired Relationship Analysis (PRA) of two PP1-PIP (WBP11 and CD2BP2) of example 2; wherein the size of the dots represents the number of matching proteins, and the color of the dots or squares represents the significance of the data analysis; c is the activity map of protein kinase CLKs and CDKLs in three subtypes of ESCC;
in fig. 5 a-c are the mean mouse body weight and mean tumor volume (+ -s.e.m.) volume curves for ESCC PDX model #1-3 treated with control (PBS) and CLK1 inhibitor TG003 in example 2, arrows indicate the time of drug treatment; d is the detection of mRNA levels of the enhancers CD2BP2 and WBP11 of CLK1 kinase in PDX model by Realtime-PCR.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
The embodiment of the invention provides application of an agent for inhibiting activity of protein kinase CLK in preparation of a medicine for treating or improving esophageal squamous cell carcinoma.
The inventor finds that the activity of protein kinase CLK in ESCC tumor tissues is abnormally increased compared with that of tissues beside cancer through a series of creative researches, and particularly, the activity is obvious in patients with higher malignancy degree. The Esophageal Squamous Cell Carcinoma (ESCC) with high malignancy degree is mainly characterized in that protein phosphorylation in a spliceosome (spidiosome) signal pathway is abnormally active, and a protein kinase CLK plays a key role in the spliceosome signal pathway.
And by inhibiting the activity of the protein kinase CLK, the protein kinase CLK can effectively inhibit or improve ESCC, and provides a new target and a new research direction for the precise treatment of ESCC.
The "drug" herein may be selected from all types of existing drugs, without limitation; the medicine can be classified according to forms and can be divided into liquid dosage forms, solid dosage forms, semisolid dosage forms and gas dosage forms; classified according to a dispersion system (a system in which particles of one or more substances are dispersed in another substance is called a dispersion system, a dispersed substance is called a dispersion phase, and a substance containing the dispersion phase is called a dispersion medium or dispersion medium), and classified into a true solution type formulation, a colloidal solution type formulation, an emulsion type formulation, a suspension type formulation, a gas dispersion type formulation, and a solid dispersion type formulation; the administration route and method can be classified into a gastrointestinal administration form and a parenteral administration form; parenteral dosage forms include: injection, respiratory tract, skin and mucosa.
As used herein, "tissue adjacent to cancer" means tissue 2-5 cm from the lesion.
Preferably, the agent that inhibits protein kinase CLK activity is selected from at least one of inhibitor 1 and inhibitor 2;
wherein the inhibitor 1 is an agent for inhibiting the activity of protein kinase CLK; the inhibitor 2 is an agent for inhibiting activity of a protein kinase CLK enhancer.
Herein, "an agent for inhibiting the activity of protein kinase CLK" means an agent capable of directly inhibiting the activity of protein kinase CLK, "an agent for inhibiting the activity of a protein kinase CLK enhancer" means an agent which exerts an effect of inhibiting the activity of protein kinase CLK by inhibiting the activity of a protein kinase CLK enhancer.
In some embodiments, inhibitor 1 and inhibitor 2 are not subject to any limitation, as long as an agent capable of directly or indirectly inhibiting the activity of protein kinase CLK is used in the preparation of a medicament for treating or improving ESCC, and is within the scope of the present invention.
Preferably, the inhibitor 1 is selected from: at least one of TG003, KH-CB19 and ML 16.
Preferably, the inhibitor 2 is selected from at least one of a CD2BP2 inhibitor and a WBP11 inhibitor.
Expression levels of CD2BP2 protein and WBP11 protein were also abnormally increased in ESCC tumor tissues relative to paraneoplastic tissues. Both CD2BP2 and WBP11 can inhibit the activity of protein phosphatase PP1, and the inventor finds that the two protein-regulated phosphorylated proteins mainly correspond to substrates of protein kinase CLK, namely CD2BP2 and WBP11 can be used as protein enhancers of protein kinase CLK. And the activity of at least one protein of CD2BP2 and WBP11 is inhibited, so that the enhancement effect of the CD2BP2 and/or WBP11 protein on the activity of the protein kinase CLK can be indirectly prevented or reduced, and the aim of reducing the activity of the protein kinase CLK is fulfilled.
Optionally, the protein kinase CLK is selected from at least one of CLK1, CLK2, CLK3, and CLK 4.
The embodiment of the invention also provides application of the CD2BP2 inhibitor in preparing a reagent for inhibiting activity of protein kinase CLK.
The embodiment of the invention also provides application of the WBP11 inhibitor in preparing an agent for inhibiting activity of protein kinase CLK.
The embodiment of the invention also provides application of the CD2BP2 inhibitor in preparing a medicament for treating or improving esophageal squamous cell carcinoma.
The embodiment of the invention also provides application of the WBP11 inhibitor in preparing a medicament for treating or improving esophageal squamous cell carcinoma.
The embodiment of the invention also provides application of a reagent for detecting the expression level of a target gene in preparing a reagent for detecting esophageal squamous cell carcinoma, wherein the target gene is at least one selected from CD2BP2 and WBP 11.
As used herein, detecting the "expression level of a gene of interest" may refer to detecting the expression level of the gene of interest in tumor tissue or tissue adjacent to cancer.
The embodiment of the invention also provides application of an agent for detecting the expression level of a target gene in screening of medicines for treating or improving esophageal squamous cell carcinoma, wherein the target gene is selected from at least one of CD2BP2 and WBP 11;
such use is not directly aimed at the diagnosis or treatment of disease.
It should be noted that both CD2BP2 and WBP11 can be used as molecular markers for targeted therapy of ESCC, especially molecular markers for targeted therapy of ESCC using CLK1 kinase inhibitor, which can directly improve pharmaceutical efficiency and drug effectiveness, increase therapeutic effectiveness of ESCC, and improve survival rate of ESCC patients.
The features and properties of the present invention are described in further detail below with reference to examples.
Example 1
This example performed mass spectrometry analysis of the proteome and phosphorylation modification groups of 94 ESCC tumor samples, which were classified into three subtypes based on proteomic characteristics (a in FIG. 1).
Among these, subtype III with the lowest disease-free survival (b in FIG. 1) is characterized by elevated levels of proteomes and phosphoproteomes in the spliceosome signaling pathway (a in FIG. 1).
The expression of CD2BP2 and WBP11 proteins in tumors of different subtypes is detected, and the result is shown in FIG. 2. As can be seen from FIG. 2, the expression of CD2BP2 and WBP11 proteins was significantly upregulated in subtype III tumors compared to other subtypes.
And functional experiments show that the two proteins have important effects on the proliferation of esophageal cancer cells. In vitro CCK8 experiments showed that both CD2BP2 and WBP11 knockdown significantly inhibited growth of ESCC cells (KYSE150 and KYSE30) (fig. 3).
Example 2
The effect of CD2BP2 and WBP11 on protein kinase CLK was verified.
The phosphatase and kinase Paired Relationship Analysis (PRA) analysis showed that the phosphorylated proteins regulated by the negative regulators of PP1 (CD2BP2 and WBP11) mainly correspond to substrates for the enzyme CLK (fig. 4, a).
Thus, CD2BP2 and WBP11 may be considered as enhancer proteins of CLK kinase. Meanwhile, the results showed that CD2BP2 and WBP11 proteins were expressed at the highest level among subtypes III of ESCC, consistent with CLK kinase activity being also highest at subtype III (b in fig. 4).
Example 3
The effect of the CLK kinase inhibitor on ESCC was verified.
This example examined the effect of inhibitor TG003 on tumors using the CLK kinase specific inhibitor TG003 in a xenograft model (PDX model) of tumors from three ESCC patients, and the results are shown in FIG. 5.
As can be seen from a to c in fig. 5, the CLK kinase-specific inhibitor TG003 showed the best inhibitory effect in PDX # 2, but also showed a certain inhibitory effect in the PDX # 1 model.
In PDX model II, where the CLK kinase specific inhibitor TG003 inhibited most significantly, the CLK kinase enhancer proteins CD2BP2 and WBP11 were expressed at the highest levels, while in the other two PDX models CD2BP2 and WBP11 were expressed at the general levels (d in fig. 5).
In conclusion, the invention provides the application of the reagent for inhibiting the activity of protein kinase CLK in preparing the medicine for treating or improving esophageal squamous cell carcinoma, the application takes CLK kinase as a target molecule for treating ESCC, and the aim of effectively treating or improving ESCC can be achieved by inhibiting the activity of CLK.
In addition, the activity of the CLK kinase is the highest in ESCC with higher malignancy, and for the part of patients, the CLK kinase inhibitor can achieve the aim of targeted therapy.
The invention also finds that the inhibitory proteins CD2BP2 and WBP11 of two protein phosphatases PP1 can be used as a CLK kinase activity enhancer, can be used as a molecular marker for guiding CLK kinase inhibitor targeted therapy in the future, and achieves the aim of accurate therapy.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. Use of an agent that inhibits the activity of protein kinase CLK in the manufacture of a medicament for the treatment or amelioration of esophageal squamous cell carcinoma.
2. Use of an agent that inhibits the activity of protein kinase CLK according to claim 1 in the manufacture of a medicament for treating or ameliorating esophageal squamous cell carcinoma, wherein the agent that inhibits the activity of protein kinase CLK is selected from at least one of inhibitor 1 and inhibitor 2;
wherein the inhibitor 1 is an agent for inhibiting the activity of protein kinase CLK; the inhibitor 2 is an agent for inhibiting activity of a protein kinase CLK enhancer.
3. Use of an agent inhibiting the activity of protein kinase CLK according to claim 2 in the manufacture of a medicament for the treatment or amelioration of esophageal squamous cell carcinoma, wherein inhibitor 1 is selected from the group consisting of: at least one of TG003, KH-CB19 and ML 16;
preferably, the inhibitor 2 is selected from at least one of a CD2BP2 inhibitor and a WBP11 inhibitor.
4. Use of an agent inhibiting the activity of protein kinase CLK according to claim 2 in the manufacture of a medicament for treating or ameliorating esophageal squamous cell carcinoma, wherein the protein kinase CLK is selected from at least one of CLK1, CLK2, CLK3 and CLK 4.
Use of an inhibitor of CD2BP2 in the preparation of an agent for inhibiting the activity of protein kinase CLK.
Use of a WBP11 inhibitor for the preparation of an agent for inhibiting the activity of protein kinase CLK.
Use of an inhibitor of CD2BP2 in the manufacture of a medicament for the treatment or amelioration of esophageal squamous cell carcinoma.
Use of an inhibitor of WBP11 in the manufacture of a medicament for treating or ameliorating esophageal squamous cell carcinoma.
9. Use of a reagent for detecting the expression level of a target gene in the preparation of a reagent for detecting esophageal squamous cell carcinoma, wherein the target gene is at least one selected from the group consisting of CD2BP2 and WBP 11.
10. Use of an agent for detecting the expression level of a gene of interest for screening a medicament for treating or ameliorating esophageal squamous cell carcinoma, wherein the gene of interest is at least one selected from the group consisting of CD2BP2 and WBP 11; such use is not directly aimed at the diagnosis or treatment of disease.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116004830A (en) * | 2023-01-05 | 2023-04-25 | 山东大学 | Biomarker for ovarian cancer and application thereof |
| CN116129998A (en) * | 2023-01-19 | 2023-05-16 | 中国医学科学院肿瘤医院 | Esophageal squamous cell carcinoma data processing method and system |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107550900A (en) * | 2017-09-25 | 2018-01-09 | 中美（河南）荷美尔肿瘤研究院 | Application of the Oridonin in terms of protein kinase B inhibitor is prepared |
| CN109652545A (en) * | 2019-01-11 | 2019-04-19 | 山西医科大学 | ZNF750 is in screening for treating the purposes in esophageal squamous cell carcinoma targeted drug |
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2021
- 2021-05-08 CN CN202110500549.7A patent/CN113230405B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107550900A (en) * | 2017-09-25 | 2018-01-09 | 中美（河南）荷美尔肿瘤研究院 | Application of the Oridonin in terms of protein kinase B inhibitor is prepared |
| CN109652545A (en) * | 2019-01-11 | 2019-04-19 | 山西医科大学 | ZNF750 is in screening for treating the purposes in esophageal squamous cell carcinoma targeted drug |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116004830A (en) * | 2023-01-05 | 2023-04-25 | 山东大学 | Biomarker for ovarian cancer and application thereof |
| CN116004830B (en) * | 2023-01-05 | 2023-08-11 | 山东大学 | Biomarker for ovarian cancer and application thereof |
| CN116129998A (en) * | 2023-01-19 | 2023-05-16 | 中国医学科学院肿瘤医院 | Esophageal squamous cell carcinoma data processing method and system |
| CN116129998B (en) * | 2023-01-19 | 2024-06-11 | 中国医学科学院肿瘤医院 | Esophageal squamous cell carcinoma data processing method and system |
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