CN113368249A - OGT inhibitor and application thereof - Google Patents
OGT inhibitor and application thereof Download PDFInfo
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- CN113368249A CN113368249A CN202110633116.9A CN202110633116A CN113368249A CN 113368249 A CN113368249 A CN 113368249A CN 202110633116 A CN202110633116 A CN 202110633116A CN 113368249 A CN113368249 A CN 113368249A
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- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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- C12Q1/48—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving transferase
Abstract
The invention relates to an OGT inhibitor and application thereof. The invention provides an application of an OGT inhibitor in preventing or treating medulloblastoma or inhibiting the proliferation of medulloblastoma cells. In particular embodiments, the OGT inhibitors can inhibit the generation and cell proliferation of medulloblastoma, suggesting that OGT inhibitors have great pharmaceutical potential in preventing or treating medulloblastoma. The present invention also provides a method for screening a candidate drug for preventing or treating medulloblastoma or inhibiting the proliferation of medulloblastoma cells.
Description
Technical Field
The invention belongs to the field of biomedicine, and particularly relates to an OGT inhibitor and application thereof.
Background
Medulloblastoma (MB), a posterior fossa malignant tumor, often originates from the lumbricus cerebelli or the posterior medulla sail, has very rapid growth of tumor cells, has very high invasion and migration capacity, and is very easy to spread to the whole central nervous system through the circulation of cerebrospinal fluid. MB is the most common intracranial malignant tumor in children, and accounts for 20 percent of the central nervous system tumors in children and doubles up to 40 percent of the cerebellar tumors in children. The incidence rate of European and American white race is higher than that of Asian race, the sick population is more male than female, the high incidence age is 8 years old, most of the incidence occurs before 20 years old, the infant is in lactation period at minimum, and the adult is rare.
In 2007, the World Health Organization (WHO) defined it as a WHOIV grade in the central nervous system oncology classification criteria. The clinical manifestations of medulloblastoma are mainly symptoms of increased intracranial pressure, headache is accompanied with continuous vomiting, the signs of ataxia appear when the tumor compresses cerebellum, and the tumor can also spread to the subarachnoid space of spinal cord with cerebrospinal fluid, so that the illness condition of patients is worsened rapidly.
The most common clinical method for treating medulloblastoma is a method combining surgery, radiotherapy and chemotherapy. The operation is an important treatment means for medulloblastoma, can relieve hydrocephalus, reduce intracranial pressure and make a definite pathological diagnosis, and the tumor resection can obviously improve the survival rate of patients and improve prognosis. However, the marrow blastoma is very difficult to operate due to the special disease site of the marrow blastoma, the age of the patient and other reasons, and the tumor is difficult to completely clear, so that the tumor is easy to relapse after the surgical operation, the prognosis of the patient is poor, the health of the patient is seriously affected, and the survival rate of the patient after the operation for 5 years is still low. Therefore, in addition to surgical resection, combined therapy with postoperative radiation therapy is often used to significantly improve the survival rate and reduce the postoperative recurrence rate of patients, but the follow-up treatment may be the long-term toxic and side effects of the central nervous system of patients, such as hearing impairment, cognitive dysfunction, nerve and mental retardation, and the like. Therefore, it is important to find a drug or a method for effectively treating medulloblastoma.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention aims to provide an application of an OGT inhibitor in preventing or treating medulloblastoma or inhibiting the proliferation of medulloblastoma cells, thereby providing a new idea for developing a medicament for preventing or treating medulloblastoma or inhibiting the proliferation of medulloblastoma cells.
The above object of the present invention is achieved by the following technical solutions:
in a first aspect, the present invention provides an OGT inhibitor for use in the prevention or treatment of medulloblastoma or the inhibition of medulloblastoma cell proliferation.
The "OGT" refers to O-GlcNAc transferase.
"prevention" means preventing the appearance of medulloblastoma or the recurrence of lost medulloblastoma in a subject at risk of developing the disease. By "treating" is meant controlling, reducing or alleviating the pathological progression of medulloblastoma and prolonging the survival of the diseased subject. By "inhibiting the proliferation of medulloblastoma cells" is meant preventing or slowing the proliferation of medulloblastoma cells.
The present invention is not limited in any way to the subject having medulloblastoma or the species of the subject at risk of medulloblastoma, and preferably human and non-human mammals such as mice, rats, guinea pigs, cats, dogs, cows, horses, sheep, pigs, monkeys, etc.
Further, the OGT inhibitor is selected from: (1) alloxan or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof; (2) OSMI-1 or a pharmaceutically acceptable salt, stereoisomer or solvate thereof; (3) OSMI-4 or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof; (4) APNT or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof; (5) APBT or a pharmaceutically acceptable salt, stereoisomer or solvate thereof; (6) badge or a pharmaceutically acceptable salt, stereoisomer or solvate thereof; (7) ac4-5SGlcNAc or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof; (8) BZX or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.
By "pharmaceutically acceptable salt" of a compound is meant a salt of the compound that is suitable for administration to a subject for prophylactic or therapeutic purposes without causing unacceptable toxicity to the subject. Pharmaceutically acceptable salts include salts with inorganic acids (for example, salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid and phosphoric acid), salts with organic acids (for example, salts with formic acid, acetic acid, propionic acid, trifluoroacetic acid, fumaric acid, maleic acid, tartaric acid, citric acid, succinic acid, lactic acid, malic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid), salts with inorganic bases (for example, alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, and aluminum salt and ammonium salt), salts with organic bases (for example, salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine and N, N' -dibenzylethylenediamine), and salts with basic or acidic amino acids (for example, salts with basic amino acids such as arginine, lysine and ornithine, or salts with acidic amino acids such as glutamic acid and aspartic acid). The invention is not limited in the kind of pharmaceutically acceptable salts formed with the OGT inhibitors in free compound form, as long as they retain their OGT inhibitory activity.
"stereoisomers" means compounds having the same composition and molecular weight but different physical and/or chemical properties due to different arrangement of atoms of the compounds in space. Stereoisomers include enantiomers (stereoisomers that are non-superimposable mirror images of each other), diastereomers (stereoisomers that are not mirror images of each other), racemates (mixtures containing equal amounts of the individual enantiomeric forms with opposite chirality). The present invention is not limited in the kind of stereoisomer of OGT inhibitor as long as it retains inhibitory activity against OGT.
"solvate" means a solvent addition form of a compound containing a stoichiometric or non-stoichiometric amount. Certain compounds or salts thereof have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thereby forming solvates. If the solvent is water, the solvate formed is a hydrate; if the solvent is an alcohol, the solvate formed is an alcoholate. The present invention is not limited in the kind of solvate of the OGT inhibitor as long as it retains inhibitory activity against OGT.
Further, the OGT inhibitor is OSMI-1 or a pharmaceutically acceptable salt, stereoisomer or solvate thereof.
The "OSMI-1" refers to (alpha R) -alpha- [ [ (1, 2-dihydro-2-oxo-6-quinolyl) sulfonyl ] amino ] -N- (2-furylmethyl) -2-methoxy-N- (2-thienylmethyl) phenylacetamide.
Furthermore, the medulloblastoma includes WNT type medulloblastoma, SHH type medulloblastoma, Group 3 type medulloblastoma and Group 4 type medulloblastoma.
Further, the medulloblastoma is SHH-type medulloblastoma.
In a second aspect, the present invention provides a pharmaceutical composition for preventing or treating medulloblastoma or inhibiting medulloblastoma cell proliferation, the pharmaceutical composition comprising the OGT inhibitor of the first aspect.
Further, the pharmaceutical composition also comprises a pharmaceutically acceptable carrier.
By "pharmaceutically acceptable carrier" is meant a carrier suitable for formulation with an active ingredient for prophylactic or therapeutic purposes into a pharmaceutical composition for administration to a subject without causing unacceptable toxicity to the subject. For the preparation of the pharmaceutical composition, any pharmaceutically acceptable carrier commonly used in the art may be employed. For example, to prepare solid dosage forms for oral administration, solid carriers known in the art may be used. Examples of the solid carrier are fillers such as glucose, microcrystalline cellulose, lactose, starch, powdered sugar, dextrin, mannitol and the like; binders such as methylcellulose, hypromellose, carboxymethylcellulose, microcrystalline cellulose, povidone, starch slurry, mucilage, and the like; disintegrants such as croscarmellose sodium, sodium carboxymethyl starch, crospovidone, hydroxypropyl starch, etc.; lubricants such as magnesium stearate, calcium stearate, talc, and the like. In addition, coloring agents, flavoring agents, sweetening agents, preservatives and the like may also be used as long as they are compatible with the ingredients used. The pharmaceutical composition of the present invention can be prepared in the form of, for example, tablets, capsules, powders, granules, pills, etc., using the above-mentioned solid carriers.
For preparing liquid dosage forms for oral administration, liquid carriers known in the art may be used. Examples of liquid carriers are water, ethanol, propylene glycol, glycerol, dimethyl sulfoxide, polyethylene glycol, and fatty oils, liquid paraffin, ethyl oleate, isopropyl myristate, and the like. The pharmaceutical composition of the present invention can be prepared in the form of, for example, a solution, a suspension, an emulsion, a syrup, or an elixir using the above-mentioned liquid carrier.
For preparing a dosage form for parenteral administration, sterile carriers known in the art may be used. Such as water for injection, oil for injection such as vegetable oil, e.g., sesame oil, soybean oil, peanut oil, castor oil, tea oil, other solvents for injection such as ethanol, propylene glycol, glycerin, polyethylene glycol, benzyl benzoate, ethyl oleate, dimethylacetamide, and the like. In addition, additives such as solubilizers, wetting agents, emulsifiers, suspending agents, buffers, antioxidants, chelating agents, and the like may be used in order to facilitate the preparation of injectable dosage forms. For sterile powders for injection, fillers and preservatives such as lactose, sucrose, maltose, mannitol, glycine, human serum albumin and the like can also be used.
The pharmaceutical compositions of the present invention may be administered by any suitable route of administration, for example, oral, parenteral (including intravenous, intradermal, subcutaneous, intramuscular, intraperitoneal and the like), topical (including sublingual), rectal, vaginal routes and the like. It will be appreciated that the preferred route of administration will depend upon the age, sex, weight, general medical condition of the subject to be treated, the nature and severity of the condition to be treated, the potency of the active ingredient employed and the like.
In a third aspect, the invention provides the use of an OGT inhibitor according to the first aspect of the invention or a pharmaceutical composition according to the second aspect of the invention in the manufacture of a medicament for the prevention or treatment of medulloblastoma or for inhibiting the proliferation of medulloblastoma cells.
Furthermore, the dosage form of the medicine comprises tablets, capsules, granules, pills, dripping pills, syrup, powder, suppositories, drops, emulsions, injection, solutions or suspensions.
In a fourth aspect, the present invention provides a method for screening a candidate drug for preventing or treating medulloblastoma or inhibiting medulloblastoma cell proliferation, the method comprising the steps of:
1) testing the enzymatic activity or level of OGT in the presence or absence of a test agent;
2) comparing the enzymatic activity or level of OGT in the presence or absence of the test agent to determine a change in the enzymatic activity or level of OGT caused by the test agent;
3) screening for a test agent that reduces the enzymatic activity or level of OGT, which is indicative of a candidate drug for preventing or treating medulloblastoma or inhibiting medulloblastoma cell proliferation.
Furthermore, the medulloblastoma includes WNT type medulloblastoma, SHH type medulloblastoma, Group 3 type medulloblastoma and Group 4 type medulloblastoma.
Further, the medulloblastoma is SHH-type medulloblastoma.
In a fifth aspect, the present invention provides a kit for screening a candidate drug for preventing or treating medulloblastoma or inhibiting medulloblastoma cell proliferation, the kit comprising a reagent for detecting the enzymatic activity or level of OGT.
Furthermore, the medulloblastoma includes WNT type medulloblastoma, SHH type medulloblastoma, Group 3 type medulloblastoma and Group 4 type medulloblastoma.
Further, the medulloblastoma is SHH-type medulloblastoma.
In a sixth aspect, the invention provides a method of inhibiting medulloblastoma cell proliferation for non-therapeutic purposes, said method comprising administering to a subject in need thereof an OGT inhibitor according to the first aspect of the invention or a pharmaceutical composition according to the second aspect of the invention.
A seventh aspect of the invention provides the use of any one of:
(1) use of OGT in screening for a candidate drug for preventing or treating medulloblastoma or inhibiting medulloblastoma cell proliferation;
(2) use of OGT in the manufacture of a kit for screening a candidate drug for preventing or treating medulloblastoma or inhibiting medulloblastoma cell proliferation.
Further, the application (1) of the seventh aspect of the present invention comprises:
1) testing the enzymatic activity or level of OGT in the presence or absence of a test agent;
2) comparing the enzymatic activity or level of OGT in the presence or absence of the test agent to determine a change in the enzymatic activity or level of OGT caused by the test agent;
3) screening for a test agent that reduces the enzymatic activity or level of OGT, which is indicative of a candidate drug for preventing or treating medulloblastoma or inhibiting medulloblastoma cell proliferation.
Furthermore, the medulloblastoma includes WNT type medulloblastoma, SHH type medulloblastoma, Group 3 type medulloblastoma and Group 4 type medulloblastoma.
Further, the medulloblastoma is SHH-type medulloblastoma.
The invention has the following advantages and beneficial effects:
the invention discovers for the first time that the OGT inhibitor can inhibit the generation and proliferation of medulloblastoma cells and has good medicinal potential in the aspect of preventing or treating medulloblastoma.
The present invention also provides a method for screening a candidate drug for preventing or treating medulloblastoma or inhibiting the proliferation of medulloblastoma cells.
Drawings
FIG. 1 is a graph showing the results of experiments in which OSMI-1 inhibits the generation of SHH subtype medulloblastoma, wherein A is a survival curve of DMSO and OSMI-1 gavage treated M-Smo tumor mice; FIG. B is a photograph of HE staining of the cerebellum part of M-Smo tumor mouse P30 treated by DMSO and OSMI-1 gavage; panel C is a statistical plot of the cerebellar brain weights of DMSO and OSMI-1 gavage treated M-Smo tumor mice day P30.
FIG. 2 is a graph showing the results of an experiment in which OSMI-1 inhibits the proliferation of human SHH subtype medulloblastoma DaoY cells; wherein, the graph A is a statistical graph of curves of OD values marked by DaoY cells of different treatment groups at different times of cck 8; FIG. B is a graph of immunofluorescence staining of DaoY cell proliferation markerEdU and Ki67 in different treatment groups; FIG. C is a statistical chart of the proportion of EdU-positive cells; panel D is a statistical chart of the proportion of Ki67 positive cells; panel E is a statistical plot of the staining of the DaoY single cell colony, Geemsa.
Detailed Description
The present invention is further illustrated below with reference to specific examples, which are intended to be illustrative only and are not to be construed as limiting the invention. Those of ordinary skill in the art will understand that: various changes, modifications, substitutions and alterations can be made to the embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the claims and their equivalents. The following examples are examples of experimental methods not indicating specific conditions, and the detection is usually carried out according to conventional conditions or according to the conditions recommended by the manufacturers.
Experimental materials:
example 1OSMI-1 inhibits the production of SHH subtype medulloblastoma
First, experimental material
Mice: atoh 1-Cre; SmoM2
Reagent: OSMI-1(Sigma, SmL1621)
Second, the experimental procedure
The experimental process comprises the following steps: randomly selecting Atoh1-Cre 14 days after birth; SHH type medulloblastoma tumor mice from SmoM2 were subjected to intragastric administration of OSMI-1 and the corresponding volume of solvent DMSO, three days after the administration. The survival curves of the two groups of mice were counted and the weight of the brains of the two groups of mice was compared when measuring P30.
Specific experimental operations:
1. mouse hybridization: firstly, choosing OGTF/FHybridizing with Atoh1-Cre to obtain Atoh 1-Cre; OGT (one glass solution)F/-heterozygotes, simultaneously hybridizing SmoM2 and Atoh1-Cre to obtain Atoh 1-Cre; SmoM2 heterozygotes, and then the two heterozygote mice are further hybridized to obtain Atoh 1-Cre; OGT (one glass solution)F/-；SmoM2F/-By combining Atoh 1-Cre; OGT (one glass solution)F/-；SmoM2F/-Hybridizing to obtain Atoh 1-Cre; SmoM2 (tumor model mouse-M-Smo).
2. M-Smo mice administration treatment: M-Smo tumor model mice of P14 days were randomly selected, and were administered with DMSO and OSMI-1 gavage, respectively, with DSMO as a control group and OSMI-1 as an experimental group. Three days after continuous irrigation, and stopping for one day, wherein the dosage is 180 mu g of OSMI-1 and 9 mu of LDMSO once per mouse.
3. HE staining: selecting M-Smo tumor mice which are full of 30 days and are treated by DMSO and OSMI-1 intragastric administration, taking the whole brain tissue after PFA perfusion, fixing the whole brain tissue in PFA for 24 hours, and performing gradient dehydration by using 10%, 20% and 30% sucrose. Frozen sections with a thickness of 20 μm. Brain slices from similar sites were selected and washed three times with PBS. Fixing with 95% ethanol for 20min, washing with PBS for 3 times, each for 5 min. Staining with hematoxylin staining solution for 2-3min, and washing with tap water. Eosin staining for 1min, washing with tap water. Drying brain slice or naturally drying, sealing with neutral resin, and removing.
4. Survival curve: the time to death was counted for M-Smo tumor mice treated with DMSO and OSMI-1 gavage, at least 10 mice per genotype, and survival curves were calculated using Prism software.
5. Mouse cerebellum weight statistics: dissecting the M-Smo tumor mouse which is subjected to intragastric administration more than 30 days after birth, obtaining cerebellum tissues and weighing, and counting the obtained data by Prism software.
Third, experimental results
As shown in FIG. 1, OSMI-1 was able to inhibit the generation of medulloblastoma when the survival time of the mice treated with the M-Smo tumor was longer than that of the control group, and the weight of the cerebellum of the mice treated with the M-Smo tumor was significantly lower than that of the control group (the data are expressed as the mean. + -. standard error; P is < 0.05).
Example 2 OSMI-1 inhibits the proliferation of human SHH subtype medulloblastoma DaoY cells
First, experimental material
Cell: DaoY (ATCC)
Reagent: OSMI (Sigma, Sml1621), Thiamet-G (Sigma, Sml0244), Ki67(BD, 550609), EdU detection kit (Ruibo), Jimsa dye liquor (pley), cck8 dye liquor (Novozam) two, experimental procedures
The experimental process comprises the following steps: cultured DaoY cells are treated with DMSO, OSMI-1 and Thiamet-G, and the five groups of cells are subjected to cell proliferation marker Ki-67 immunofluorescence detection and EdU infiltration experiments, and simultaneously subjected to Giemsa staining of single-cell colonies and cck8 cell proliferation detection experiments.
Specific experimental operations:
1. differently treated DaoY cells propagated markerEdU and Ki67 markers: EdU staining was done according to the Protocol of the EdU labeling kit. Groups of DaoY cells were seeded in a confocal dish and DMSO and different concentrations of the OGT inhibitor OSMI-1 and the OGA inhibitor Thiamet-G were added to the medium. The cells in the DMSO-treated group were grown to a coverage of 50% -80% and removed from the incubator, discarded, fixed with PFA at room temperature for 20min, and washed three times with PBS for 5min each. Acetone was fixed for 10 min at 4 ℃ and washed three times with PBS, 5min each. 2mg/mL glycine wash for 10 min. 0.5% PBST was decolorized for 10 minutes. PBS was washed three times for 5 minutes each. Apollo dye was stained for 40 minutes at room temperature, washed with 0.5% PBST for 10 minutes, treated with methanol for 5 minutes, and washed with PBS three times. After EdU labeling was completed, 10% NGS (China fir gold bridge) was blocked for 1h at room temperature 20 minutes after punching with 1% PBST at room temperature. Primary antibody (1: 400 diluted in 5% NGS) was incubated overnight at 4 ℃. After rewarming the primary antibody at room temperature for 1h, the antibody was washed three times with PBS, 5 minutes each time. Secondary antibody (1: 500 diluted in 5% NGS) was incubated for 3 hours and then washed five times in PBS for 5 minutes each, DAPI mounting.
2. DaoY cell single cell colony giemsa staining: preparing Agar solution according to the mass volume ratio of 5%, sterilizing at high temperature, cooling to 40 ℃, preparing a solid culture medium with the DaoY cell complete culture medium incubated at 37 ℃ according to the volume ratio of 1:20, pouring the mixed culture medium into a cell dish with the thickness of 60mm as soon as possible, wherein the volume of each dish is about 2mL, and placing an incubator at 37 ℃ for later use. A concentration of 32 cells/mL of medium was added to the dishes already containing the clotting medium, 3mL of medium containing DaoY cells was added to each dish, and DMSO and various concentrations of OSMI-1 and Thiamet-G were given to the medium and gently mixed. The culture was carried out in an incubator at 37 ℃ and 0.5mL of the medium was added to each dish every three days. After culturing for 21 days, abandoning the culture medium, adding 1mLPBS, slightly shaking and cleaning twice, adding 2mL of giemsa staining solution, staining for 15-30 minutes at 37 ℃ (the staining time can be adjusted according to the staining depth), adding 1mLPBS, slightly shaking and cleaning, repeating for three times, airing and photographing, and counting the formation rate of single cell colonies.
3. Cck8 detection of DaoY cell proliferation: DaoY cells were plated in 96-well plates at 1000 cells per well, 200. mu.L of medium was added to each well, DMSO and different concentrations of OSMI-1 and Thiamet-G were added simultaneously, mixed gently, and cultured at 37 ℃. Then 20 mu Lck 8 dye solution is added into each well after 48h, 72h, 96h, 120h and 144h of culture, and the absorbance OD value is measured at 450nm after 2h of incubation at 37 ℃.
Third, experimental results
As shown in FIG. 2, OSMI-1 can inhibit the proliferation of human SHH subtype medulloblastoma DaoY cells. All data are expressed as mean ± sd, n is 3, and P is < 0.05. Denotes P value < 0.001.
The preferred embodiments of the present application have been described in detail with reference to the accompanying drawings, however, the present application is not limited to the details of the above embodiments, and various simple modifications can be made to the technical solution of the present application within the technical idea of the present application, and these simple modifications are all within the protection scope of the present application.
It should be noted that, in the foregoing embodiments, various features described in the above embodiments may be combined in any suitable manner, and in order to avoid unnecessary repetition, various possible combinations are not described in the present application.
In addition, any combination of the various embodiments of the present application is also possible, and the same should be considered as disclosed in the present application as long as it does not depart from the idea of the present application.
Claims (10)
1. An OGT inhibitor for use in the prevention or treatment of medulloblastoma or the inhibition of medulloblastoma cell proliferation.
2. The OGT inhibitor of claim 1, wherein the OGT inhibitor is selected from the group consisting of: (1) alloxan or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof; (2) OSMI-1 or a pharmaceutically acceptable salt, stereoisomer or solvate thereof; (3) OSMI-4 or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof; (4) APNT or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof; (5) APBT or a pharmaceutically acceptable salt, stereoisomer or solvate thereof; (6) badge or a pharmaceutically acceptable salt, stereoisomer or solvate thereof; (7) ac4-5SGlcNAc or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof; (8) BZX or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof;
preferably, the OGT inhibitor is OSMI-1 or a pharmaceutically acceptable salt, stereoisomer or solvate thereof.
3. The OGT inhibitor according to claim 1 or 2, wherein the medulloblastoma comprises WNT type medulloblastoma, SHH type medulloblastoma, Group 3 type medulloblastoma, Group 4 type medulloblastoma, preferably the medulloblastoma is SHH type medulloblastoma.
4. A pharmaceutical composition for preventing or treating medulloblastoma or inhibiting medulloblastoma cell proliferation, comprising the OGT inhibitor of any one of claims 1-3.
5. Use of an OGT inhibitor as claimed in any one of claims 1 to 3 or a pharmaceutical composition as claimed in claim 4 in the manufacture of a medicament for the prevention or treatment of medulloblastoma or for inhibiting the proliferation of medulloblastoma cells.
6. The use of claim 5, wherein the medicament is in the form of tablets, capsules, granules, pills, syrups, powders, suppositories, drops, emulsions, injections, solutions or suspensions.
7. A method of screening for a candidate agent for preventing or treating medulloblastoma or inhibiting medulloblastoma cell proliferation, the method comprising the steps of:
1) testing the enzymatic activity or level of OGT in the presence or absence of a test agent;
2) comparing the enzymatic activity or level of OGT in the presence or absence of the test agent to determine a change in the enzymatic activity or level of OGT caused by the test agent;
3) screening for a test agent that reduces the enzymatic activity or level of OGT, which is indicative of a candidate drug for preventing or treating medulloblastoma or inhibiting medulloblastoma cell proliferation;
preferably, the medulloblastoma includes WNT medulloblastoma, SHH medulloblastoma, Group 3 medulloblastoma, and Group 4 medulloblastoma, and preferably, the medulloblastoma is SHH medulloblastoma.
8. A kit for screening a candidate drug for preventing or treating medulloblastoma or inhibiting medulloblastoma cell proliferation, wherein the kit comprises a reagent for detecting the enzymatic activity or level of OGT, preferably, the medulloblastoma comprises WNT type medulloblastoma, SHH type medulloblastoma, Group 3 type medulloblastoma, Group 4 type medulloblastoma, preferably, the medulloblastoma is SHH type medulloblastoma.
9. A method of inhibiting medulloblastoma cell proliferation for non-therapeutic purposes, comprising administering the OGT inhibitor of any one of claims 1-3 or the pharmaceutical composition of claim 4 to a subject in need thereof.
10. Use according to any one of the following:
(1) use of OGT in screening for a candidate drug for preventing or treating medulloblastoma or inhibiting medulloblastoma cell proliferation;
(2) use of OGT in the manufacture of a kit for screening a candidate drug for preventing or treating medulloblastoma or inhibiting medulloblastoma cell proliferation;
preferably, the medulloblastoma includes WNT medulloblastoma, SHH medulloblastoma, Group 3 medulloblastoma, and Group 4 medulloblastoma, and preferably, the medulloblastoma is SHH medulloblastoma.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114306617A (en) * | 2022-01-30 | 2022-04-12 | 中国科学技术大学 | Small molecule inhibitor for promoting glioma stem cell apoptosis and application thereof |
| CN115192709A (en) * | 2022-05-12 | 2022-10-18 | 黄淮学院 | Use of an inhibitor of O-GlcNAc glycosyltransferase for the manufacture of a medicament for the inhibition of spermatogenesis |
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| CN112891540A (en) * | 2021-01-28 | 2021-06-04 | 滨州医学院 | Application of OGT (one glass solution) as target in preparation of medicine for treating abnormal glucagon secretion in diabetes |
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| CN112891540A (en) * | 2021-01-28 | 2021-06-04 | 滨州医学院 | Application of OGT (one glass solution) as target in preparation of medicine for treating abnormal glucagon secretion in diabetes |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114306617A (en) * | 2022-01-30 | 2022-04-12 | 中国科学技术大学 | Small molecule inhibitor for promoting glioma stem cell apoptosis and application thereof |
| CN115192709A (en) * | 2022-05-12 | 2022-10-18 | 黄淮学院 | Use of an inhibitor of O-GlcNAc glycosyltransferase for the manufacture of a medicament for the inhibition of spermatogenesis |
| CN115192709B (en) * | 2022-05-12 | 2023-07-21 | 黄淮学院 | Use of an O-GlcNAc glycosyltransferase inhibitor in the preparation of a medicament for inhibiting spermatogenesis |
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