CN115364224A - Use of GLUT1 inhibitors as inducers of mitophagy - Google Patents
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Abstract
The application discloses a use of a GLUT1 inhibitor as a mitochondrial autophagy inducer. The application provides a novel application of a GLUT1 inhibitor as a mitophagy inducer, and in a preferred embodiment of the invention, BAY-876 and STF-31 can be used as the mitophagy inducer and have outstanding capacity of selectively inducing and damaging mitophagy.
Description
Technical Field
The invention relates to the field of chemical drugs, in particular to application of a GLUT1 inhibitor as a mitophagy inducer.
Background
Glucose transporter 1 (GLUT 1) inhibitors are commonly used to inhibit the proliferation of cancer cells, such as lung and breast cancer cells, by glucose transporter 1 expression levels.
Mitochondria serve as energy metabolism centers in cells, and regulate cell death and inflammation. The quality of mitochondria is controlled by cells through mitochondrial autophagy, so that the normal physiological process of the cells is ensured and the level of inflammation is reduced. Mitophagy, an important physiological process in cells, is closely related to the occurrence and development of various diseases. Such as neurodegenerative diseases, inflammation, autoimmune diseases, infectious diseases, etc. The mechanisms by which these diseases are treated remain unclear and no effective treatment is available in the prior art. The inventor finds in research that during the development process of diseases related to mitophagy, mitochondria are dysfunctional, damage accumulation is generated, the mitophagy dysfunction is further aggravated, and cells cannot inhibit inflammation or other symptoms by removing damaged mitochondria, so that the disease progression is inhibited. At this time, induction of mitochondrial autophagy can effectively help cells restart the mitochondrial quality control process, thereby removing damaged mitochondria, alleviating disease symptoms and hopefully curing such refractory diseases.
However, there has been no success in developing a mitochondrial autophagy inducer suitable for clinical treatment. Therefore, there is a need in the art to develop new mitophagy inducers.
Disclosure of Invention
The invention aims to provide application of a GLUT1 inhibitor.
Another object of the present invention is to provide a method for inducing mitophagy.
Another object of the present invention is to provide a method for preventing and/or treating diseases associated with mitophagy.
To solve the above technical problems, the present invention provides in a first aspect the use of a GLUT1 inhibitor for the preparation of a medicament or pharmaceutical composition for one or more uses selected from the group consisting of:
(i) (ii) inducing mitophagy (as a mitophagy inducer); and
(ii) Preventing and/or treating diseases associated with mitochondrial autophagy.
In some preferred embodiments, the induced mitophagy is a mitophagy that selectively induces damage, more preferably a mitophagy that selectively induces damage caused by CCCP.
In some preferred embodiments, the GLUT1 inhibitor is BAY-876 or STF-31.
In some preferred embodiments, the selectively inducing impaired mitophagy comprises:
selectively induces the degradation of the damaged mitochondrial marker protein Tim23, but has no influence on the degradation of the endoplasmic reticulum marker protein Calnexin.
In some preferred embodiments, the selectively inducing impaired mitophagy comprises:
selectively enhance the fluorescence of the keima protein localized in the damaged mitochondria, but not affect the fluorescence intensity of the keima protein in the undamaged mitochondria.
In some preferred embodiments, the disease associated with mitophagy is selected from at least one of ischemia-reperfusion injury, neurodegenerative disease, kidney injury-related disease, cardiac disease, and sepsis.
In some preferred embodiments, the neurodegenerative disease is selected from at least one of Alzheimer's Disease (AD), huntington's Disease (HD), parkinson's Disease (PD), amyotrophic Lateral Sclerosis (ALS), hypoxic ischemic brain injury, MELAS-type Mitochondrial Encephalomyopathy (MELAS), and diclosterous convulsion-associated disease.
In some preferred embodiments, the kidney injury-related disease is selected from at least one of acute kidney injury, diabetic nephropathy, and chronic renal failure.
In some preferred embodiments, the heart disease is selected from at least one of cardiomyopathy, diabetic cardiomyopathy, and cardiovascular disease.
In some preferred embodiments, the ischemia-reperfusion injury is selected from at least one of renal ischemia-reperfusion injury, hepatic ischemia-reperfusion injury, and cardiac ischemia-reperfusion injury or cerebral ischemia-reperfusion injury.
In a second aspect of the invention, there is provided a pharmaceutical composition comprising BAY-876 and STF-31, and a pharmaceutically acceptable carrier or excipient.
In a third aspect of the present invention, there is provided a method of inducing mitochondrial autophagy, the method comprising the steps of:
administering to the subject a mitophagy inducer which is a GLUT1 inhibitor or a pharmaceutical composition according to the second aspect of the invention.
In some preferred embodiments, the induced mitophagy is selectively induced impaired mitophagy.
In some preferred embodiments, the GLUT1 inhibitor is BAY-876 or STF-31.
In a fourth aspect of the present invention, there is provided a method for preventing and/or treating a disease associated with mitophagy, the method comprising the steps of:
administering to the subject a therapeutically effective amount of a GLUT1 inhibitor or a pharmaceutical composition according to the second aspect of the invention.
Compared with the prior art, the invention has at least the following advantages:
(1) The invention provides a novel application of a GLUT1 inhibitor as a mitophagy inducer, and in a preferred embodiment of the invention, BAY-876 and STF-31 can be used as the mitophagy inducer and have outstanding capacity of selectively inducing and damaging mitophagy;
(2) The invention also provides methods of treating mitophagy-related afflictions including neurodegenerative diseases, kidney injury-related diseases, cardiac diseases, sepsis and the like using GLUT1 inhibitors, preferably BAY-876 and STF-31.
(3) The invention also provides a pharmaceutical composition which can be used for selectively inducing the damaged mitochondrion autophagy and simultaneously contains BAY-876 and STF-31.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Drawings
One or more embodiments are illustrated by the figures in the accompanying drawings, which correspond to and are not intended to limit the embodiments.
FIG. 1 is a graph showing the results of Tim23 and Calnexin contents of cells containing damaged mitochondria and undamaged mitochondria under BAY-876 treatment in accordance with an embodiment of the present invention;
FIG. 2 is a statistical heat map of fluorescence images of cells containing damaged mitochondria and undamaged mitochondria treated with BAY-876 and STF-31, respectively, in accordance with an embodiment of the present invention.
Detailed Description
Existing research and development efforts have demonstrated that mitophagy is associated with the pathological progression of a variety of problematic diseases. Glucose transporter 1 (GLUTs) is the major carrier for mediating glucose transport in mammalian cells, and its subtype GLUT1 is most widely distributed in vivo glucose transporters. The existing research shows that the expression level of GLUT1 is increased and has different degrees of correlation with various cancers, so the GLUT1 inhibitor is used for resisting cancers in the prior art. The inventor of the present invention has found through extensive and intensive studies that a GLUT1 inhibitor (for example, BAY-876 or STF-31) can act as an autophagy inducing agent for mitochondria to induce autophagy or repair the pathway of autophagy, and thus can be used for preventing and/or treating diseases associated with autophagy for mitochondria.
GLUT1 inhibitors
In the present invention, the GLUT1 inhibitor refers to a compound, polypeptide, and protein that can inhibit the expression of glucose transporter 1. Commercial GLUT1 inhibitors are commercially available, and it will be understood by those skilled in the art that GLUT1 inhibitors useful herein are not limited to the compounds WZB117, DRB18, KL-11743, BAY-876, and STF-31 disclosed herein.
In a preferred embodiment of the invention, the GLUT1 inhibitor is the compound BAY-876 or STF-31.
In the invention, the structural formula of the compound BAY-876 is shown as a formula I, wherein the literature name is as follows: n4- (1- (4-cyanophenylmethyl) -5-methyl-3- (trifluoromethyl) -1H-pyrazol-4-yl) -7-fluoroquinoline-2, 4-dicarboxamide having the CAS number: 1799753-84-6.BAY-876 can be used as GLUT1 inhibitor.
In the invention, the structural formula of the compound 'STF-31' is shown as formula II, wherein the text name is as follows: 4- [ 4-tert-butylphenyl ] sulfonyl ] amino ] methyl ] -N-3-pyridylbenzamide having the CAS number: 724741-75-7.STF-31 can be used as GLUT1 inhibitor.
In the present invention, the structural formula of the compound "WZB117" is shown as formula III, wherein the text name is: 3-fluoro-1, 2-phenylenebis (3-hydroxybenzoate), CAS No.: 1223397-11-2.WZB117 can be used as GLUT1 inhibitor.
In the present invention, the structural formula of the compound "DRB18" is shown in formula IV. DRB18 can be used as GLUT1 inhibitor.
In the invention, the structural formula of the compound 'KL-11743' is shown as a formula V, wherein the text name is as follows: acetamide, 2- [3- [ 6-ethoxy-4- [4- (1H-pyrazolyl-4-yl) phenyl ] amino ] -2-quinazolinyl ] phenoxy ] -N- (1-methylethyl) -, CAS number: 1369452-53-8.KL-11743 can be used as GLUT1 inhibitor.
Mitophagy inducer
In the present invention, the mitophagy inducer is a compound that can selectively degrade the autophagy pathway in damaged mitochondria (e.g., CCCP-damaged mitochondria). The mitophagy pathway includes recognition of damaged mitochondria, activation of mitophagy receptors, encapsulation of damaged mitochondria by autophagosomes, fusion of autophagosomes with lysosomes, degradation of mitochondria by lysosomes, and the like. The mitophagy inducer may play a role in multiple processes.
Pharmaceutical composition
In the present invention, the pharmaceutical composition comprises an active ingredient, and a pharmaceutically acceptable carrier or excipient; wherein the active ingredient comprises BAY-876 and/or STF-31.
In a preferred embodiment of the present invention, the active ingredients comprise BAY-876 and STF-31.
As used herein, "active ingredient" refers to a compound that is administered to a subject, either alone or in combination with one or more pharmaceutically acceptable excipients, to treat, prevent or alleviate one or more symptoms of a condition, disorder or disease. As used herein, "active ingredient" and "active substance" may be a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, isotopic variation or tautomer of a compound described herein.
As used herein, "pharmaceutically acceptable carriers and excipients" refer to pharmaceutically acceptable materials, compositions or vehicles, such as liquid or solid fillers, diluents, solvents or encapsulating materials. In one embodiment, each component is "pharmaceutically acceptable," meaning that it is compatible with the other components of the pharmaceutical formulation and is suitable for use in contact with the tissues or organs of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications commensurate with a reasonable benefit/risk ratio.
The pharmaceutical compositions of the present invention may be formulated with pharmaceutically acceptable carriers and/or vehicles as described above, ultimately providing several forms of unit dosage form and multi-dose form. Non-limiting examples of the formulations include, but are not limited to, oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups and aerosols, external preparations such as ointments and creams, suppositories, and sterile injectable solutions, preferably oral formulations or sterile injectable solutions.
Use of
The GLUT1 inhibitors of the invention may be used in the preparation of a medicament or pharmaceutical composition for one or more uses selected from the group consisting of:
(i) Inducing mitophagy;
(ii) Preventing and/or treating diseases associated with mitophagy.
In a preferred embodiment of the present invention, the induction of mitophagy is the selective induction of injured mitophagy, and more preferably the selective induction of injured mitophagy by CCCP.
In the present invention, the term "inducing mitochondrial autophagy" refers to inducing targeted phagocytosis or destruction of mitochondria by cells.
In the present invention, the term "selectively inducing damaged mitochondrial autophagy" refers to an autophagy mode that selectively isolates and degrades damaged or incomplete mitochondria, without affecting or only minimally affecting undamaged mitochondria.
In a preferred embodiment of the invention, the GLUT1 inhibitor is BAY-876 or STF-31. Both have outstanding ability to selectively induce impaired mitophagy, i.e. to selectively induce impaired mitophagy, compared to other GLUT1 inhibitors.
In a preferred embodiment of the present invention, BAY-876 or a pharmaceutical composition containing the same, STF-31 or a pharmaceutical composition containing the same, BAY-876 and STF-31, and a pharmaceutical composition containing BAY-876 and STF-31 all have an outstanding ability to selectively induce impaired mitophagy.
"selectivity" can be verified by various means conventional in the art. In a preferred embodiment of the present invention, the selectively inducing impaired mitophagy comprises: selectively enhance the fluorescence of the keima protein localized in the damaged mitochondria, but not affect the fluorescence intensity of the keima protein in the undamaged mitochondria. In another preferred embodiment of the present invention, the selectively inducing damaged mitophagy comprises: selectively induces the degradation of the damaged mitochondrial marker protein Tim23, but has no influence on the degradation of the endoplasmic reticulum marker protein Calnexin.
Indications of
In the present invention, GLUT1 inhibitors are useful for the prevention and/or treatment of diseases associated with mitophagy. Such as neurodegenerative diseases, diseases associated with renal injury, cardiac diseases, sepsis, etc.
Neurodegenerative diseases such as, without limitation, alzheimer's Disease (AD), huntington's Disease (HD), parkinson's Disease (PD), amyotrophic Lateral Sclerosis (ALS), hypoxic ischemic brain injury, MELAS-type Mitochondrial Encephalomyopathy (MELAS), and disorders associated with convulsions, and the like.
Kidney injury related diseases such as, but not limited to, acute kidney injury, diabetic nephropathy, and chronic renal failure, and the like.
Cardiac diseases such as but not limited to cardiomyopathy, diabetic cardiomyopathy, and cardiovascular disease.
Method of treatment
In the present invention, the method for treating the above indications comprises the steps of: a therapeutically effective amount of a GLUT1 inhibitor, preferably BAY-876, STF-31, or a pharmaceutical composition of the invention is administered to the subject.
In the present invention, the term "subject" is defined herein to include animals, such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, and the like. In a particular embodiment, the subject is a human.
To accommodate the characteristics of the subject and the therapeutic requirements, the mode of administration of the "GLUT1 inhibitor" or "pharmaceutical composition" to the subject is not limited in the present invention, and alternative modes of administration include: enterally (oral, sublingual, rectal), parenterally (intravenous, subcutaneous, intramuscular, intraperitoneal), by pulmonary absorption, or by conjunctival, nasopharyngeal, buccal, rectal, urethral, or bladder absorption, and in one embodiment enterally to a subject.
As used herein, a "therapeutically effective amount" of a compound is that amount of the compound which is sufficient to provide a therapeutic effect, or to delay or minimize one or more symptoms associated with a disease or disorder, in the treatment or management of the disease or disorder. A therapeutically effective amount of a compound refers to the amount of therapeutic agent that, when used alone or in combination with other therapies, provides a therapeutic effect in the treatment or management of a disease or disorder. The term "therapeutically effective amount" can include an amount that improves overall therapy, reduces or avoids symptoms or causes of a disease or disorder, or enhances the therapeutic efficacy of another therapeutic agent.
In the present invention, a safe and effective amount of a "GLUT1 inhibitor" or a "pharmaceutical composition" is administered to a subject, where the safe and effective amount is 10 to 2000mg/kg, preferably 10 to 100 mg/kg; for example: 10mg/kg, 20mg/kg, 30mg/kg, 40mg/kg, 50mg/kg, 100mg/kg, the safe and effective amounts are the contents of the active ingredients. In some embodiments, the safe and effective amount is 50-200mg/kg (mouse), or 500-1000mg/kg (human).
The frequency of administration of the "GLUT1 inhibitor" or "pharmaceutical composition" according to the invention is from 1 to 3 times daily, e.g. 1 time in the morning or evening, 2 times each in the morning and evening or 3 times each in the morning, noon, evening; the administration is continued for not less than 1 day, preferably not less than 3 days, preferably not less than 5 days, preferably not less than 7 days, most preferably not less than 7 days.
In order to make the objects, technical solutions and advantages of the embodiments of the present invention more apparent, the present invention is further described below with reference to specific embodiments. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Experimental procedures without specific conditions noted in the following examples, generally according to conventional conditions, or according to conditions recommended by the manufacturer. Unless otherwise indicated, percentages and parts are percentages and parts by weight. The test materials and reagents used in the following examples are commercially available without specific reference.
Unless otherwise defined, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs, and it is to be noted that the terms used herein are merely for describing particular embodiments and are not intended to limit exemplary embodiments of the present application.
Example 1, immunohybridization assay to verify that HEK293T cells (purchased from ECACC) that specifically induce selective mitophagy development by BAY-876 and STF-31 were seeded in 6-well plates at a density of 2 × 105/ml, 2ml per well. 6 wells were seeded per cell. After 24 hours, BAY-876 or STF-31 was added at a final concentration of 5. Mu.M without and with 3. Mu.M CCCP (Carbonyl cyanide3-chlorophenylhydrazone, causing mitochondrial damage), respectively. After 12 hours the samples were pooled with 250. Mu.l of 2XSDS loading buffer. Heating at 100 deg.C for 10 min.
Immune hybridization: each sample is loaded with 10 mul and electrophoresed for 90V2h; transfer film 300mA,1h.5% skim milk was blocked at room temperature for 1h, and the antibody (Tim 23 antibody from Proteintetech, #11123-1-AP; tubulin antibody from Huaan biotechnology, hangzhou, # M1305-2 calnexin antibody from Cell Signaling Technology, # 2433S) was incubated overnight at 4 degrees at a dilution ratio (1 for Tubulin antibody, 5000, and 1 for the remainder) with PBST (phosphate buffer +0.1 tween 20) washing 3 times for 10 minutes each. Secondary antibody (coat anti-Mouse IgG (H + L) secondary antibody from Thermo Fisher Scientific, # 31430: 20000 dilutions were incubated for 1h at room temperature and PBST washed 3 times for 10 min each. And (4) ECL color development.
As shown in figure 1, the immune hybridization (western blot) detection shows that BAY-876 and STF-31 do not cause the degradation of the mitochondrial marking protein Tim23 and do not affect the degradation of the endoplasmic reticulum marking protein Calnexin in HEK293T cells. In case of mitochondrial damage caused by CCCP addition, BAY-876 and STF-31 resulted in degradation of the mitochondrial marker protein Tim23, but did not affect degradation of the endoplasmic reticulum marker protein Calnexin. This suggests that BAY-876 and STF-31 specifically induce the development of selective mitochondrial autophagy without affecting the development of other autophagies.
Example 2 Keima fluorescence detection assay to verify that BAY-876 induces selective mitophagy
Human embryonic kidney transformed cell HEK293Tmtkeima cell (which can indicate the occurrence of mitophagy, the cell line of mtkeima stable expression is constructed by self, the biological preservation information is CCTCC NO: C201940 2019.03.07) is planted in a 96-hole black enzyme label plate at 1.5 x 105/ml, BAY-876 or STF-31 with the final concentration of 5 mu M is added, and 3 times of repetition are set; cultured at 37 ℃ 5% CO2. Another group of cells under the same conditions, human embryonic kidney transformed cells HEK293Tmtkeima cells at 1.5 x 105/ml in 96-well black plate, each 100 u l; adding 3 μ M CCCP to induce mitochondrial damage after 24 hr, adding BAY-876 or STF-31 with final concentration of 5 μ M after 1 hr, and repeating for 3 times; at 37 ℃ C, 5% CO 2 The culture conditions were incubated, and pictures were taken after 12 hours using biotek cycle 5. The two groups are both used as focusing channels in a bright field, 4 pictures are taken in each hole, and the images are processed by instrument software.
As shown in FIG. 2, the human embryonic kidney transformed cell HEK293Tmtkeima system, treated with 3uM CCCP to induce mitochondrial damage and then with BAY-876 or STF-31, significantly increased keima signaling compared to treatment with BAY-876 or STF-31 alone. And no significant increase in keima signal was seen after treatment with BAY-876 alone. Indicating that BAY-876 does not cause mitochondrial damage and selectively induces mitophagy in damaged mitochondria.
It will be understood by those of ordinary skill in the art that the foregoing embodiments are specific examples for carrying out the invention, and that various changes in form and details may be made therein without departing from the spirit and scope of the invention in practice.
Claims (9)
- Use of a glut1 inhibitor for the preparation of a medicament or pharmaceutical composition for one or more uses selected from the group consisting of:(i) Inducing mitophagy;(ii) Preventing and/or treating diseases associated with mitophagy.
- 2. The use according to claim 1, wherein the GLUT1 inhibitor is selected from at least one of WZB117, DRB18, KL-11743, BAY-876, and STF-31.
- 3. The use of claim 1, wherein the GLUT1 inhibitor is BAY-876 or STF-31.
- 4. Use according to claim 1, wherein the induced mitophagy is a selective induction of impaired mitophagy, more preferably a selective induction of impaired mitophagy by CCCP.
- 5. Use according to claim 1 or 2, wherein the disease associated with mitophagy is selected from at least one of ischemia-reperfusion injury, neurodegenerative disease, kidney injury-related disease, cardiac disease and sepsis.
- 6. The use according to claim 5, wherein the neurodegenerative disease is selected from at least one of Alzheimer's Disease (AD), huntington's Disease (HD), parkinson's Disease (PD), amyotrophic Lateral Sclerosis (ALS), hypoxic ischemic brain injury, MELAS-type Mitochondrial Encephalomyopathy (MELAS), and a diconvulsive related disease; and/orThe kidney injury-related disease is selected from at least one of acute kidney injury, diabetic nephropathy and chronic renal failure; and/orThe heart disease is selected from at least one of cardiomyopathy, diabetic cardiomyopathy and cardiovascular disease; and/orThe ischemia-reperfusion injury is selected from at least one of renal ischemia-reperfusion injury, hepatic ischemia-reperfusion injury, and cardiac ischemia-reperfusion injury or cerebral ischemia-reperfusion injury.
- 7. A pharmaceutical composition comprising BAY-876 and/or STF-31, and a pharmaceutically acceptable carrier or excipient.
- 8. A method of inducing mitophagy, comprising the steps of:administering a GLUT1 inhibitor or the pharmaceutical composition of claim 7 to a subject.
- 9. A method for preventing and/or treating a disease associated with mitophagy, comprising the steps of:administering a GLUT1 inhibitor or the pharmaceutical composition of claim 7 to a subject.
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