Application of abesilib in medicine for treating glioma

Abstract

The invention discloses an application of abesilib in a glioma treatment drug, and aims to determine CHD2 as a new glioma treatment target for the first time around CHD2 which is a potential treatment target, and deeply explore the application potential of a small molecule compound abesilib in the glioma treatment drug. The virtual docking technology is fully utilized to accelerate the drug research and development process, the application of the new target is expected to significantly improve the pertinence and effect of treatment, and a new hope is brought to glioma patients; the drug screening and optimizing process is obviously accelerated, and the research and development cost and time are reduced.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine technology, and specifically relates to the application of abemaciclib in the treatment of glioma. Background Art

[0002] Glioma is the most common invasive primary malignant tumor of the central nervous system, and its treatment currently faces huge challenges. The prognosis of this disease is extremely severe. For decades, the median overall survival of patients has been hovering around 15 months, and the 5-year survival rate is less than 5%. In recent years, with the accelerated pace of life and the increasing work pressure, the incidence of glioma has shown a clear upward trend. Its extremely high mortality rate not only brings great physical and mental harm to patients, causing their quality of life to decline significantly, but also brings heavy economic and psychological burdens to patients' families. Therefore, research on the treatment of glioma is particularly urgent and important.

[0003] At present, the standard treatment strategy for gliomas mainly includes surgical resection, followed by combined radiotherapy and chemotherapy to achieve the best therapeutic effect. Among this series of treatment methods, temozolomide, as the first-line clinical drug for glioma treatment, has shown relatively good therapeutic effects. However, temozolomide has strong toxic side effects, and patients are prone to develop drug resistance to it. These problems often lead to glioma recurrence, which greatly reduces the treatment effect. Therefore, finding new and more effective chemotherapy drugs has become a top priority.

[0004] Drug repurposing, as an innovative drug discovery approach, has received widespread attention in recent years. There are many types of drugs in clinical practice, and the number of drugs is huge. These drugs constitute a rich compound library, which provides the possibility of screening new drugs with potential for treating glioma. Compared with the traditional new drug development process, drug repurposing can significantly shorten the research and development cycle and reduce research and development costs. It is worth noting that the traditional drug screening process is often time-consuming, labor-intensive and inefficient. However, with the rapid development of big data and computational science, virtual drug screening technology has emerged and is favored by many researchers. This technology can quickly and accurately screen potential candidate drugs by simulating the interaction between drugs and targets, bringing new hope to the treatment of glioma.

[0005] Small molecule compounds have always been an important source of drugs for treating malignant diseases such as gliomas. Their unique chemical structure and biological activity provide a broad space for drug research and development. Abemaciclib, an innovative drug approved by the FDA in 2017, has significant therapeutic potential. As a dual inhibitor of cell cycle-dependent protein kinases 4 (CDK4) and 6 (CDK6), it plays a key role in cell cycle regulation and can effectively inhibit the growth and proliferation of cancer cells. Clinical studies have shown that the use of abemaciclib can significantly improve the survival rate of breast cancer patients, providing a new treatment option for this intractable disease. In addition, abemaciclib has also shown good application prospects in the treatment of melanoma, lymphoma and various solid tumors, and its wide range of therapeutic potential has attracted widespread attention from researchers and clinicians. However, although abemaciclib has shown significant effects in the treatment of various tumors, its role in the treatment of gliomas and its specific mechanism have not yet been reported.

[0006] In the study of high-grade glioma, it was found that CHD2 can regulate the interaction between neurons and gliomas, and plays a key role in the progression of the disease. Inhibiting the activity of CHD2 will damage the vitality of cells and lead to abnormal synaptic connections between neurons and gliomas in vitro. This discovery provides new ideas for the treatment of gliomas. Particularly striking is that in the H3.1K27M diffuse midline glioma mouse model, inhibiting CHD2 significantly prolonged the survival rate of mice, further confirming the value of CHD2 as a potential therapeutic target. Summary of the invention

[0007] Technical issues solved:

[0008] The present application aims at the deficiencies in the prior art and solves the technical problems faced by current glioma drugs in treatment, such as limited efficacy and drug resistance, strong toxic side effects of temozolomide, and patients are prone to develop drug resistance thereto. The application of abemaciclib in the treatment of glioma is provided. With abemaciclib as the core, the potential of abemaciclib to regulate CHD2 in glioma patients is provided, providing new drugs for the development of glioma treatment.

[0009] Technical solution:

[0010] To achieve the above objectives, this application is implemented through the following technical solutions:

[0011] The use of abemaciclib in the treatment of gliomas.

[0012] Furthermore, the therapeutic drug for glioma comprises abemaciclib and pharmaceutically acceptable excipients.

[0013] Furthermore, the auxiliary materials include one or more of excipients, diluents, fillers, binders, wetting agents, disintegrants, absorption promoters, surfactants, adsorption carriers, and lubricants.

[0014] Furthermore, the therapeutic drug for glioma is in an oral dosage form or a non-oral dosage form.

[0015] Furthermore, the therapeutic drug for glioma is in the form of tablets, capsules, powders, pills, granules, solutions, suspensions, syrups, injections, suppositories, inhalants or sprays.

[0016] Beneficial effects:

[0017] The present application provides the use of abemaciclib in the treatment of glioma, which has the following beneficial effects compared with the prior art:

[0018] 1. As a dual inhibitor of CDK4 / 6, abemaciclib has shown significant effects in regulating the cell cycle and inhibiting the growth of cancer cells. Combined with the new target CHD2, the potential application of abemaciclib in the treatment of gliomas is proposed to achieve drug repositioning;

[0019] 2. This application will conduct an in-depth study on whether abemaciclib can interfere with the growth and progression of glioma by affecting CHD2 or related pathways, providing a new therapeutic drug option for this intractable disease;

[0020] 3. This application uses protein virtual docking technology and the advanced virtual docking technology AutoDock-Vina-GPU to screen a large number of small molecule compounds, and virtually screen and optimize CHD2, and discovers a new glioma treatment drug abemaciclib with higher activity and lower toxic side effects, and successfully predicts the binding free energy of abemaciclib with CHD2, which significantly accelerates the drug screening and optimization process;

[0021] 4. This application focuses on CHD2 as a potential therapeutic target. It identifies CHD2 as a new target for glioma treatment for the first time, deeply explores the application potential of the small molecule compound abemaciclib in glioma treatment drugs, and makes full use of virtual docking technology to accelerate the drug development process. The application of this new target is expected to significantly improve the pertinence and effect of treatment, bringing new hope to glioma patients;

[0022] 5. By using advanced virtual docking technology, the present invention successfully screened out drugs with low binding free energy to CHD2 from a large number of small molecule compounds, significantly accelerating the process of drug screening and optimization, and reducing R&D costs and time;

[0023] 6. Abemaciclib in this application was originally used as a dual inhibitor of CDK4 / 6 and has been used in the treatment of various cancers; the present invention further explores its potential application in the treatment of gliomas, realizes the repositioning and expanded application of drugs, and provides new treatment options for glioma patients. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 is the structural formula of abemaciclib of the present application;

[0025] Figure 2 is a virtual docking free energy score distribution diagram of the small molecule drug of the present application, wherein A is a virtual docking free energy score scatter diagram and a violin diagram, and B is a virtual docking free energy distribution bar diagram;

[0026] Figure 3 It is the top 10 drug graphs of virtual docking free energy scores of small molecule drugs in this application;

[0027] Figure 4 is a docking conformation diagram of abemaciclib and CHD2 of the present application, wherein A is an overall docking conformation diagram, and B is a local conformation diagram of abemaciclib located at the docking center;

[0028] Figure 5 This is a diagram of the docking structure binding pattern of abemaciclib and CHD2 in the present application. DETAILED DESCRIPTION

[0029] In this section, the specific embodiments of this patent application will be described in detail in conjunction with the accompanying drawings, aiming to provide a clear and comprehensive description of the technical solution. It should be clear that the embodiment described here only represents one of the possible applications of this patent and does not represent all possible implementation methods. Based on the content of this document, a person of ordinary skill in the art can derive all other potential embodiments covered by this application without performing any creative work. Therefore, these embodiments should all be deemed to be within the scope of protection of this patent.

[0030] Example 1

[0031] The CHD2 protein structure was obtained by AlphaFold2 (https: / / alphafold.ebi.ac.uk / ) AI prediction, and the small molecule 3D structure was obtained from the ZINC20 database (https: / / zinc.docking.org / ); the potential complex between the protein and the small molecule was calculated by AutoDock-Vina-GPU (https: / / github.com / DeltaGroupNJUPT / Vina-GPU-2.1); before the calculation, the protein structure was refined to remove non-binding substances and add hydrogen bonds, and it was set as a rigid receptor; the small molecule was set as a ligand molecule that allows flexible torsion to more accurately simulate its binding process with the protein. To determine the size and position of the docking box, AutoDockTools (https: / / autodocksuite.scripps.edu / adt / ) was used to generate a size of The 3D docking box is centered on the predicted spatial position of the ligand. Subsequently, AutoDock-Vina-GPU is used to perform 9 simulation calculations on each small molecule, and the result with the lowest free energy is selected as the possible complex structure. Finally, the predicted results of all small molecules are sorted according to free energy, and small molecules that can potentially bind to proteins are successfully predicted, providing strong support for subsequent drug development and optimization.

[0032] Experimental results:

[0033] In order to directly predict the binding of clinical drugs to CHD2 protein, the human CHD2 protein structure was selected for research; the structural information of the protein was derived from the UniProt database, and the protein number was O14647·CHD2_HUMAN; AlphaFold was used to predict the spatial structure of the human CHD2 protein, and the predicted protein number was AF-O14647-F1; after obtaining the CHD2 protein structure, 1,339 FDA-class small molecule compounds were selected from the ZINC20 database as research objects; these small molecule compounds have known pharmacological activities and clinical application potential, and are very suitable for predictive research on drug binding; next, AutoDock-Vina-GPU was used to perform virtual docking experiments; by simulating the interaction between small molecule compounds and CHD2 protein, the results of complex binding free energy were obtained; after sorting and screening, the top 10 drugs were successfully listed as shown in Table 1; these drugs have the lowest binding free energy with CHD2 protein, indicating that they may have strong binding ability and potential pharmacological effects; this result provides a strong basis and direction for subsequent drug development and optimization.

[0034] Table 1

[0035]

[0036]

[0037] Example 2

[0038] Screening of abemaciclib as a potential therapeutic drug for glioma:

[0039] In the process of screening potential therapeutic drugs for glioma, a comprehensive analysis and investigation of the predicted small molecules was carried out; by comparing the binding free energy of these small molecules with the CHD2 protein, the top 10 drugs were successfully selected; these 10 drugs showed strong binding ability with the CHD2 protein, indicating that they may have potential therapeutic effects on glioma; in-depth screening and analysis are needed to further verify the efficacy of these drugs; this application pays special attention to those drugs that can effectively treat tumor-related diseases; by comprehensively evaluating the binding free energy, pharmacokinetic properties and existing clinical research data of the drugs, this application successfully screened out abemaciclib as a potential drug for the treatment of glioma.

[0040] Experimental results:

[0041] Among the top 10 drugs in the prediction score, 5 are closely related to cancer treatment. Among them, cabozantinib, nilotinib, imatinib and lapatinib, as tyrosine kinase inhibitors, have shown significant effects in the treatment of various cancers. These drugs play an important role in the treatment of advanced renal cell carcinoma, hepatocellular carcinoma, medullary thyroid carcinoma and advanced metastatic breast cancer. In addition, studies have shown that cabozantinib, as a leader in its class, has also shown significant effects in the treatment of high-grade gliomas, which further confirms the potential of tyrosine kinase inhibitors in cancer treatment. However, among these 5 drugs, enzalutamide, as an androgen receptor inhibitor, can effectively treat prostate cancer, but due to the specificity of its target, it is not suitable as an alternative drug for the treatment of gliomas. Therefore, in the screening of therapeutic drugs for gliomas, abemaciclib, as a dual inhibitor of CDK4 / 6, has shown excellent performance in the treatment of various cancers. Combined with the results of virtual docking, it was found that abemaciclib can play its potential role in glioma treatment drugs by binding to the CHD2 receptor.

[0042] The above description has fully disclosed the specific embodiments of the present invention. It should be pointed out that any changes made by those skilled in the art to the specific embodiments of the present invention do not deviate from the scope of the claims of the present invention. Accordingly, the scope of the claims of the present invention is not limited to the above specific embodiments.

Claims

1. The application of abemaciclib in the treatment of glioma.

2. The use according to claim 1, characterized in that: The therapeutic drug for glioma comprises abemaciclib and pharmaceutically acceptable excipients.

3. The use according to claim 2, characterized in that: Excipients include one or more of excipients, diluents, fillers, binders, wetting agents, disintegrants, absorption promoters, surfactants, adsorption carriers, and lubricants.

4. The use according to claim 1, characterized in that: The therapeutic drugs for glioma are oral or parenteral dosage forms.

5. The use according to claim 1, characterized in that: Therapeutic drugs for glioma are tablets, capsules, powders, pills, granules, solutions, suspensions, syrups, injections, suppositories, inhalants or sprays.

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