KR102361078B1 - Pharmaceutical composition for preventing or treating of cancer comprising Malate Aspartate Shuttle inhibitor and Carnitine Acylcarnitine Carrier Shuttle inhibitor - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for preventing or treating cancer and an anticancer adjuvant comprising a malic acid-aspartic acid transport inhibitor and a carnitine acylcarnitine transporter transport inhibitor. Therefore, the present invention can significantly inhibit the growth of cancer cells compared to the case of using a malate-aspartate shuttle (Malate Aspartate Shuttle) inhibitor or a Carnitine Acylcarnitine Carrier Shuttle inhibitor alone.

Description

TECHNICAL FIELD [0001] Pharmaceutical composition for preventing or treating cancer comprising Malate-aspartate transport inhibitor and Carnitine Acylcarnitine Carrier Shuttle inhibitor and Carnitine Acylcarnitine Carrier Shuttle inhibitor

The present invention relates to a pharmaceutical composition for preventing or treating cancer and an anticancer adjuvant comprising a malic acid-aspartic acid transport inhibitor and a carnitine acylcarnitine transporter transport inhibitor.

Cancer is largely classified into blood cancer and solid cancer, and occurs in almost all parts of the body. Currently, surgery, radiation therapy, and chemotherapy using chemicals that inhibit cell proliferation are mainly used as treatment methods. However, the biggest problems of existing chemical anticancer drug treatment are side effects due to cytotoxicity and drug resistance, which are the main factors that ultimately cause the treatment using chemical anticancer drugs to fail. Therefore, as a therapeutic agent to replace chemical anticancer drugs, there is a continuous need for the development of a target therapeutic agent with a clear anticancer action mechanism.

Accordingly, several studies are being conducted to develop targeted therapeutics, and among them, studies on specific molecular biological factors involved in tumor formation are being actively conducted. In particular, the molecular biological factors are being studied and used in various fields, such as predicting the prognosis of cancer or determining whether to undergo chemotherapy or radiotherapy.

Malate-aspartate shuttle (MAS) refers to a system in which electrons generated in glycolysis pass through the inner mitochondrial membrane to perform oxidative phosphorylation. NADH is used for ATP production through the mitochondrial electron transport chain, but NADH cannot directly cross the mitochondrial inner membrane. Therefore, by moving electrons through MAS to produce NADH in the mitochondrial matrix, the mitochondria can ultimately synthesize ATP.

Carnitine Acylcarnitine Carrier (CAC or Carnitine Acylcarnitine Translocase; CACT) is a transport protein belonging to the inner mitochondrial membrane. CAC plays a role in transporting carnitine-fatty acid complex and carnitine to the inner mitochondrial membrane, and is essential for mitochondrial oxidation of fatty acids and survival of living things.

It is known that methylation and inhibition of arginine 248 of malate dehydrogenase 1 used in the MAS system can inhibit the proliferation of pancreatic ductal adenocarcinoma (PDAC) cells. (Molecular Cell 64, 1-15, November 17, 2016).

However, it has not been studied or disclosed whether the inhibition of the MAS system and the CAC simultaneously inhibits the growth of cancer cell lines.

Accordingly, as a result of the present inventors' efforts to provide a targeted therapeutic agent capable of significantly inhibiting the growth of cancer cell lines, an inhibitor of the malate-aspartate shuttle (MAS) system and a carnitine acylcarnitine transporter (Carnitine Acylcarnitine) Carrier; CAC) transport inhibitor was confirmed to significantly inhibit the growth of cancer cell lines compared to the case of treatment alone, and completed the present invention.

Accordingly, an object of the present invention is malate-aspartate transport (Malate Aspartate Shuttle) inhibitors; and Carnitine Acylcarnitine Carrier Shuttle inhibitors; It is to provide a pharmaceutical composition for the prevention or treatment of cancer, including an anticancer adjuvant.

In order to achieve the above object, the present invention provides a malate-aspartate transport (Malate Aspartate Shuttle; MAS) inhibitor; And carnitine acylcarnitine transporter transport (Carnitine Acylcarnitine Carrier Shuttle) inhibitor; may provide a pharmaceutical composition for preventing or treating cancer, including.

According to a preferred embodiment of the present invention, the malic acid-aspartic acid transport inhibitor is phenyl succinic acid (Phenyl Succinic Acid), methyl malonic acid (Methyl Malonic Acid), butyl malonic acid (Butyl malonic acid), maleimide (Maleimide) , N-phenyl maleimide, N-(1-pyrenyl)maleimide, N-phenyl maleamic acid, eosin- 5-maleimide (eosin-5-maleimide), Phthalonic Acid, Methyl 3-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)-propanamido ) benzoate (Methyl 3-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)-propanamido)benzoate), 3-[[2-[4-(1-admantyl)phenoxy) Cy]acetyl]amino]-4-hydroxybenzoate (Methyl 3-[[2-[4-(1-adamantyl)phenoxy]acetyl]amino]-4-hydroxybenzoate), 2-tenoyl-trifluoroacetone ( 2-Thenoyl-trifluoroacetone, chlorothricin, aminooxyacetic acid (AOA), hydrazinosuccinate, 2-amino-3-butenoic acid (2-amino-3-butenoic acid) and bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (Bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2- yl)ethyl sulfide, BPTES) may be any one or more selected from the group consisting of.

According to a preferred embodiment of the present invention, the carnitine acylcarnitine transporter transport inhibitor is omeprazole, trimetazidine, perhexiline, etomoxir, meldonium. , salts, precursors, hydrates, solvates, derivatives thereof, and biological equivalents thereof may be at least one selected from the group consisting of.

According to a preferred embodiment of the present invention, the malic acid-aspartic acid transport inhibitor and the carnitine acylcarnitine transporter transport inhibitor may be included in a molar concentration ratio of 50:1 to 1:50.

According to a preferred embodiment of the present invention, the malic acid-aspartic acid transport inhibitor and the carnitine acylcarnitine transporter transport inhibitor may be administered simultaneously or sequentially.

According to a preferred embodiment of the present invention, the malic acid-aspartic acid transport inhibitor and the carnitine acylcarnitine transporter transport inhibitor may be administered in a mg/kg (mpk) ratio of 20:1 to 1:20.

According to a preferred embodiment of the present invention, the cancer may be any one or more cancers selected from the group consisting of colon cancer, lung cancer, stomach cancer, breast cancer, brain cancer, melanoma, prostate cancer, ovarian cancer, kidney cancer, pancreatic cancer and liver cancer have.

The present invention also relates to malate-aspartate transport (Malate Aspartate Shuttle) inhibitors; And carnitine acylcarnitine transporter transport (Carnitine Acylcarnitine Carrier Shuttle) inhibitor; may provide an anticancer adjuvant comprising.

The present invention also includes any one or more selected from the group consisting of compounds represented by the following [Formula 1] or [Formula 2], pharmaceutically acceptable salts, precursors, hydrates, solvates, derivatives, and biological equivalents thereof It can provide a pharmaceutical composition for preventing or treating cancer;

[Formula 1]

[Formula 2]

Wherein R is at least one selected from the group consisting of hydrogen, halogen, and C1 to C5 linear or branched alkyl, and n is an integer of 1 to 5.

According to a preferred embodiment of the present invention, the cancer is one or more cancers selected from the group consisting of colon cancer, lung cancer, stomach cancer, breast cancer, brain cancer, melanoma, prostate cancer, ovarian cancer, kidney cancer, pancreatic cancer and liver cancer. can

The present invention also includes any one or more selected from the group consisting of compounds represented by the following [Formula 1] or [Formula 2], pharmaceutically acceptable salts, precursors, hydrates, solvates, derivatives, and biological equivalents thereof may provide an anticancer adjuvant;

[Formula 1]

[Formula 2]

Wherein R is at least one selected from the group consisting of hydrogen, halogen, and C1 to C5 linear or branched alkyl, and n is 1 to 5.

The present invention can significantly inhibit the growth of cancer cells compared to the case of using a malate-aspartate shuttle (Malate Aspartate Shuttle) inhibitor or a Carnitine Acylcarnitine Carrier Shuttle inhibitor alone.

1 shows a schematic diagram of a mechanism related to malate-aspartate transport (Malate Aspartate Shuttle).
2 shows a schematic diagram of the mechanism involved in Carnitine Acylcarnitine Carrier Shuttle.
3 shows the results of hERG K+ channel binding assay-cardiotoxicity evaluation of N-phenylmaleimide (KN-612).
4 shows the cell proliferation inhibitory effect of N-(1-pyrenyl)maleimide (KN-611) or N-phenylmaleimide (KN-612) on melanoma or pancreatic cancer cell lines, respectively.
5 shows the cell proliferation inhibitory effect of N-(1-pyrenyl)maleimide (KN-611) or N-phenylmaleimide (KN-612) on renal cancer cell lines, respectively.
6 shows the tumor suppressive effect of each of N-(1-pyrenyl)maleimide (KN-611) or N-phenylmaleimide (KN-612) on melanoma cell lines.
7 shows the results of confirming the cytotoxicity of N-phenylmaleimide and/or omeprazole to normal cells by cell proliferation.
8 shows the results of confirming the cytotoxicity of N-phenylmaleimide and/or omeprazole to normal cells in terms of ATP level.
9 shows the cell proliferation inhibitory effect of omeprazole alone on pancreatic cancer cell lines.
10 shows the cell proliferation inhibitory effect of N-phenylmaleimide alone on pancreatic cancer cell lines.
11 shows the cell proliferation inhibitory effect of N-phenyl maleamic acid alone on a pancreatic cancer cell line.
12 shows the cell proliferation inhibitory effect of N-phenylmaleimide alone on various cancer cell lines.
13 shows the cell proliferation inhibitory effect of N-phenylmaleimide and/or omeprazole on pancreatic cancer cell lines.
Figure 14 shows the effect of N-phenylmaleimide (N-phenylmaleimide) and / or omeprazole (omeprazole) on the ATP production level of a pancreatic cancer cell line. A represents the ATP production level after each drug treatment, and B represents the ATP production level measured 6 hours, 12 hours or 24 hours after the drug treatment.
15 shows the cell proliferation inhibitory effect of N-phenylmaleimide and/or omeprazole on various cancer cell lines.
16 shows the inhibitory effect of N-phenylmaleimide and/or omeprazole on ATP production levels on various cancer cell lines.
17 shows colorectal cancer (COLO 205), melanoma (RPMI-8226 or UACC62), lung cancer (H1975), stomach cancer (AGS), breast cancer (MDA-MB-231), brain cancer (SF539), prostate cancer (PC3), For cancer cell lines of ovarian cancer (OVCAR3), kidney cancer (ACHN), liver cancer (HUH7) and pancreatic cancer (AsPC-1), N-(1-prenyl)maleimide) and When omeprazole is treated alone or in combination, it indicates the degree of cell growth according to the treatment. For all cancer cell lines, the synergistic effect on the growth inhibitory effect of the combined treatment was observed, but among them, it was confirmed that the growth inhibitory effect of lung cancer, stomach cancer, breast cancer, brain cancer, pancreatic cancer and liver cancer cell lines was significantly increased.
18 shows the cell proliferation inhibitory effect of N-phenyl maleamic acid and/or omeprazole on pancreatic cancer cell lines.
19 shows N-phenyl against cancer cell lines of melanoma (UACC62), lung cancer (H1975), gastric cancer (AGS), glioblastoma (U87), prostate cancer (PC3), ovarian cancer (OVCAR4) and liver cancer (HUH7). When maleamic acid (N-phenyl maleamic acid) and omeprazole (omeprazole) are treated individually or in combination, the cell growth degree is indicated accordingly.
20 shows the cell proliferation inhibitory effect of N-phenyl maleamic acid and/or omeprazole on the lung cancer (H1975) cell line. Blue represents N-phenylmaleamic acid alone, yellow represents omeprazole alone, and green represents N-phenylmaleamic acid and omeprazole in combination.
21 shows the cell proliferation inhibitory effect of N-phenyl maleamic acid and/or omeprazole on a prostate cancer (PC3) cell line. Blue represents N-phenylmaleamic acid alone, yellow represents omeprazole alone, and green represents N-phenylmaleamic acid and omeprazole in combination.
22 shows the cell proliferation inhibitory effect of N-phenyl maleamic acid and/or omeprazole on gastric cancer (AGS) cell lines. Blue represents N-phenylmaleamic acid alone, yellow represents omeprazole alone, and green represents N-phenylmaleamic acid and omeprazole in combination.
23 shows the cell proliferation inhibitory effect of N-phenyl maleamic acid and/or omeprazole on the melanoma (UACC62) cell line. Blue represents N-phenylmaleamic acid alone, yellow represents omeprazole alone, and green represents N-phenylmaleamic acid and omeprazole in combination.
24 shows the cell proliferation inhibitory effect of N-phenyl maleamic acid and/or omeprazole on the glioblastoma (U87) cell line. Blue represents N-phenylmaleamic acid alone, yellow represents omeprazole alone, and green represents N-phenylmaleamic acid and omeprazole in combination.
25 shows the cell proliferation inhibitory effect of N-phenyl maleamic acid and/or omeprazole on a liver cancer (HUH7) cell line. Blue represents N-phenylmaleamic acid alone, yellow represents omeprazole alone, and green represents N-phenylmaleamic acid and omeprazole in combination.
26 shows the cell proliferation inhibitory effect of N-phenyl maleamic acid and/or omeprazole on ovarian cancer (OVCAR4) cell lines. Blue represents N-phenylmaleamic acid alone, yellow represents omeprazole alone, and green represents N-phenylmaleamic acid and omeprazole in combination.
27 shows the tumor suppressive effect of N-phenylmaleimide and/or omeprazole on a pancreatic cancer tumor xenograft mouse model.
28 shows the tumor suppressive effect of N-phenylmaleimide and/or omeprazole on a renal cancer tumor xenograft mouse model.
29 shows the tumor suppressive effect of N-phenylmaleimide and/or omeprazole on a melanoma tumor xenograft mouse model.
30 shows the tumor suppressive effect of N-phenylmaleimide and/or omeprazole on a liver cancer tumor xenograft mouse model.
31 shows the tumor suppressive effect of N-phenylmaleimide and/or omeprazole on a brain cancer tumor xenograft mouse model.
Figure 32 shows the tumor suppression effect of N-phenylmaleimide and/or omeprazole on a gastric cancer tumor xenograft mouse model.
33 shows the tumor suppressive effect of N-phenylmaleimide and/or omeprazole on a colorectal cancer tumor xenograft mouse model.
34 shows the tumor suppressive effect of N-phenylmaleimide and/or omeprazole on an ovarian cancer tumor xenograft mouse model.

Hereinafter, the present invention will be described in detail.

In the present invention, both 'CAC' and 'CACT' were used to mean a carnitine acylcarnitine transporter.

As described above, the conventional anticancer drugs used for cancer treatment have problems that side effects and drug resistance are easy to occur, so the development of anticancer targeted therapeutics as an alternative is required. Among them, research on molecular biological factors is in progress

In the case of a composition comprising a malate-aspartate shuttle (Malate Aspartate Shuttle) inhibitor and a Carnitine Acylcarnitine Carrier Shuttle inhibitor according to the present invention, cancer cell growth compared to the case of treating the two inhibitors alone It is effective as a composition for preventing or treating cancer or as an anticancer adjuvant because a significantly increased synergistic effect is generated for the inhibitory effect.

Accordingly, the present invention relates to malate-aspartate transport (Malate Aspartate Shuttle) inhibitors; And carnitine acylcarnitine transporter transport (Carnitine Acylcarnitine Carrier Shuttle) inhibitor; provides a pharmaceutical composition for preventing or treating cancer, including.

The malate-aspartate shuttle (Malate Aspartate Shuttle; MAS) inhibitor refers to a compound that inhibits the activity of a protein participating in the MAS system.

Specifically, the proteins participating in the MAS system are malate-alpha-ketoglutarate transporter (MAT; malate-a-ketoglutarate transporter), glutamate-aspartic acid transporter (GAT; glutamate-), as shown in [FIG. 1]. aspartate transporter), malate dehydrogenase 1 (MDH1; malate dehydrogenase 1), malate dehydrogenase 2 (MDH2; malate dehydrogenase 2), glutamic oxaloacetic transaminase 1 (GOT1; glutamic oxaloacetic transaminase 1) , glutamic oxaloacetic transaminase 2 (GOT2; glutamic oxaloacetic transaminase 2) and glutaminase (GLS1; glutaminase 1). The MAT is a transporter encoded by the human SLC25A11 gene, and may also be referred to as a mitochondrial 2-oxoglutarate/malate carrier protein. The GAT is a transport protein encoded by the human SLC25A12 gene, and may also be referred to as calcium-binding mitochondrial carrier protein Aralar1. In the malic acid dehydrogenase, MDH1 is present in the cytoplasm (cytosolic form), and MDH2 is present in the mitochondria (mitochondrial form). In addition, in the glutamic oxalacetic transaminase, GOT1 is present in the cytoplasm, and GOT2 is present in the mitochondria. The GOT1 and GOT2 may also be referred to as aspartate aminotransferase 1 (AST1; aspartate aminotransferase 1) and AST2, respectively. The GLS1 is an enzyme that converts glutamine into glutamate.

Among the proteins participating in the MAS system, the protein to be inhibited by the present invention is MAT, GOT1, GOT2 or GLS1, and preferably MAT is inhibited. The activity of MAT is a maleimide derivative, the activity of GOT1 or GOT2 is aminooxyacetic acid (AOA), and the activity of GLS1 is bis-2-(5-phenylacetamido-1,3, It may be inhibited with 4-thiadiazol-2-yl)ethyl sulfide (Bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide, BPTES), but is not limited thereto.

More specifically, the malic acid-aspartic acid reciprocal transport inhibitor of the present invention is phenyl succinic acid (Phenyl Succinic Acid), methyl malonic acid (Methyl Malonic Acid), butyl malonic acid (Butyl malonic acid), maleimide (Maleimide), N- N-phenyl maleimide, N-(1-pyrenyl)maleimide, N-phenyl maleamic acid, eosin-5-maleimide Mid(eosin-5-maleimide), Phthalonic Acid, Methyl 3-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)-propanamido)benzoate (Methyl 3-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)-propanamido)benzoate), 3-[[2-[4-(1-admantyl)phenoxy]acetyl ]Amino]-4-hydroxybenzoate (Methyl 3-[[2-[4-(1-adamantyl)phenoxy]acetyl]amino]-4-hydroxybenzoate), 2-thenoyl-trifluoroacetone (2-Thenoyl -trifluoroacetone), chlorothricin, aminooxyacetic acid (AOA), hydrazinosuccinate, 2-amino-3-butenoic acid (2-amino-3-butenoic acid) and bis- 2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (Bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide, BPTES), preferably at least one selected from the group consisting of, more preferably N-phenyl maleimide, N- (1-pyrenyl) maleimide (N- (1-pyrenyl) ) any one selected from the group consisting of maleimide) and N-phenyl maleamic acid More than one is preferred.

Proteins participating in the Carnitine Acylcarnitine Carrier Shuttle include carnitine (O-)acetyltransferase (CAT or CART), carnitine octanoyltransferase (COT), and carnitine palmitoyltransferase. and carnitine palmitoyltransferase (CPT1), carnitine palmitoyltransferase 2 (CPT2), or carnitine acylcarnitine transporter (CAC or CACT). The CAC is encoded by the human SLC25A20 gene.

The target to be inhibited by the Carnitine Acylcarnitine Carrier Shuttle inhibitor is Carnitine Acylcarnitine Carrier (CAC or Carnitine Acylcarnitine translocase; CACT), lipid peroxidation, β-oxidation , CPT-1, CAT or oxidative phosphorylation (OxPhos), preferably inhibiting CAC (CACT). The activity of CAC (CACT) is a UK5099 derivative, lipid peroxidation is a peroxisome inhibitor or ALDH inhibitor, β-oxidation is trimetazidine, and the activity of CPT-1 is perhexylline ( perhexiline) or etomoxir, the activity of CAT may be inhibited by meldonium, but is not limited thereto.

More specifically, the carnitine acylcarnitine transporter transport inhibitor of the present invention is omeprazole, trimetazidine, perhexiline, etomoxir, meldonium, and their It is preferably at least one selected from the group consisting of salts, precursors, hydrates, solvates, derivatives thereof, and biological equivalents thereof, and more preferably omeprazole, salts thereof, precursors, hydrates, solvates, these It is preferable that at least one selected from the group consisting of derivatives and biological equivalents thereof.

The malic acid-aspartic acid reciprocal transport inhibitor and the carnitine acylcarnitine transporter transport inhibitor of the present invention are preferably included in a molar concentration ratio of 50:1 to 1:50, more preferably 30:1 to 1:30. It is preferable to be included, and most preferably, it is preferably included in a molar concentration ratio of 20:1 to 1:20.

It is preferred that the malic acid-aspartic acid transport inhibitor and the carnitine acylcarnitine transporter transport inhibitor of the present invention be administered simultaneously or sequentially.

The malic acid-aspartic acid transport inhibitor and the carnitine acylcarnitine transporter transport inhibitor of the present invention are preferably administered in a mg/kg (mpk) ratio of 20:1 to 1:20, more preferably 10:1 to 1 It is preferably administered in a mg/kg (mpk) ratio of :10, and most preferably in a mg/kg (mpk) ratio of 5:1 to 1:5.

The cancer of the present invention is preferably any one or more cancers selected from the group consisting of colon cancer, lung cancer, stomach cancer, breast cancer, brain cancer, melanoma, prostate cancer, ovarian cancer, kidney cancer, pancreatic cancer and liver cancer, most preferably Most preferably, any one or more cancers selected from the group consisting of lung cancer, stomach cancer, breast cancer, brain cancer, pancreatic cancer and liver cancer.

The composition of the present invention may be in various oral or parenteral formulations. When formulating the composition, one or more buffers (eg, saline or PBS), antioxidants, bacteriostatic agents, chelating agents (eg, EDTA or glutathione), fillers, bulking agents, binders, adjuvants (eg, aluminum hydroxide), suspending agents, thickening agents, wetting agents, disintegrating agents or surfactants, diluents or excipients.

Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations include at least one excipient in one or more compounds, for example, starch (corn starch, wheat starch, rice starch, potato starch, etc.), calcium carbonate, sucrose, lactose, dextrose, sorbitol, mannitol, xylitol, erythritol maltitol, cellulose, methyl cellulose, sodium carboxymethylcellulose and hydroxypropylmethyl - It is prepared by mixing cellulose or gelatin. For example, tablets or dragees can be obtained by blending the active ingredient with solid excipients, grinding them, adding suitable adjuvants, and processing them into a mixture of granules.

In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid formulations for oral administration include suspensions, internal solutions, emulsions or syrups. In addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances or preservatives may be included. can In addition, in some cases, cross-linked polyvinylpyrrolidone, agar, alginic acid or sodium alginate may be added as a disintegrant, and an anti-aggregating agent, a lubricant, a wetting agent, a flavoring agent, an emulsifier, and a preservative may be additionally included. .

Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspension solutions, emulsions, lyophilized formulations, or suppositories. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin, glycerol, gelatin, and the like can be used.

The composition of the present invention may be administered orally or parenterally, and when administered parenterally, for external use; intraperitoneal, rectal, intravenous, intramuscular, subcutaneous, intrauterine dural or intracerebrovascular injection; transdermal administration; Alternatively, it may be formulated according to a method known in the art in the form of a nasal inhalant.

In the case of the injection, it must be sterilized and protected from contamination by microorganisms such as bacteria and fungi. For injection, examples of suitable carriers include, but are not limited to, water, ethanol, polyols (eg, glycerol, propylene glycol and liquid polyethylene glycol, etc.), mixtures thereof, and/or a solvent or dispersion medium containing vegetable oil. can More preferably, suitable carriers include Hanks' solution, Ringer's solution, phosphate buffered saline (PBS) with triethanolamine or isotonic solutions such as sterile water for injection, 10% ethanol, 40% propylene glycol and 5% dextrose. etc. can be used. In order to protect the injection from microbial contamination, it may further include various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In addition, in most cases, the injection may further contain an isotonic agent such as sugar or sodium chloride.

In the case of transdermal administration, forms such as ointment, cream, lotion, gel, external solution, pasta, liniment, and air are included. In the above, transdermal administration means that an effective amount of the active ingredient contained in the pharmaceutical composition is delivered into the skin by topically administering the pharmaceutical composition to the skin.

In the case of administration by inhalation, the compounds for use according to the invention may be administered in pressurized packs or using a suitable propellant, for example, dichlorofluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. It can be conveniently delivered in the form of an aerosol spray from the nebulizer. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. For example, gelatin capsules and cartridges for use in inhalers or insufflators may be formulated to contain a powder mixture of the compound and a suitable powder base such as lactose or starch.

The composition of the present invention is administered in a pharmaceutically effective amount. A pharmaceutically effective amount means an amount sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level is the patient's disease type, severity, drug activity, drug sensitivity, and administration time. , administration route and excretion rate, duration of treatment, factors including concomitant drugs, and other factors well known in the medical field. The composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or multiple times. That is, the total effective amount of the composition of the present invention may be administered to a patient as a single dose, and may be administered by a fractionated treatment protocol in which multiple doses are administered for a long period of time. . In consideration of all of the above factors, it is important to administer an amount that can obtain the maximum effect with a minimum amount without side effects, which can be easily determined by those skilled in the art.

The composition of the present invention can be used alone or in combination with methods using surgery, radiation therapy, hormone therapy, chemotherapy, and biological response modifiers.

The pharmaceutical composition of the present invention may also be provided in the form of an external preparation comprising a malic acid-aspartic acid reciprocating transport inhibitor and a carnitine acylcarnitine transporter transport inhibitor as active ingredients. When the pharmaceutical composition for preventing and treating allergic diseases of the present invention is used as an external preparation for skin, in addition, fatty substances, organic solvents, solubilizers, thickeners and gelling agents, emollients, antioxidants, suspending agents, stabilizers, and foaming agents (foaming agents) agent), fragrance, surfactant, water, ionic emulsifier, non-ionic emulsifier, filler, sequestering agent, chelating agent, preservative, vitamin, blocker, wetting agent, essential oil, dye, pigment, hydrophilic active agent, lipophilic It may contain adjuvants commonly used in the field of dermatology, such as active agents or any other ingredients commonly used in external preparations for skin, such as lipid vesicles. In addition, the above ingredients may be introduced in an amount generally used in the field of dermatology.

When the pharmaceutical composition for preventing and treating allergic diseases of the present invention is provided as an external preparation for skin, it may be in the form of an ointment, patch, gel, cream or spray, but is not limited thereto.

Therefore, the malic acid-aspartate transport (Malate Aspartate Shuttle; MAS) inhibitor of the present invention; and a carnitine acylcarnitine transporter (Carnitine Acylcarnitine Carrier Shuttle) inhibitor; when a cancer cell line is treated with a pharmaceutical composition for preventing or treating cancer, a significantly increased cancer cell growth inhibitory effect is obtained compared to the case of treatment alone can In this case, the control used for comparison of the cancer cell growth inhibitory effect is a medium treated with a vehicle solvent, and the vehicle may be DW (1%), DMSO (0.1% to 0.2%) or SMSO (0.1%).

In addition, the present invention provides a malate-aspartate transport (Malate Aspartate Shuttle; MAS) inhibitor; And carnitine acylcarnitine transporter transport (Carnitine Acylcarnitine Carrier Shuttle) inhibitor; provides an anticancer adjuvant comprising.

The anticancer adjuvant of the present invention refers to any form for enhancing the anticancer effect of an anticancer agent or suppressing or improving the side effects of an anticancer agent. The anticancer adjuvant of the present invention may be administered in combination with various types of anticancer agents or anticancer adjuvants, and when administered in combination, even if the anticancer agent is administered at a level lower than the dose of a conventional anticancer agent, the same level of anticancer therapeutic effect may be exhibited, so it is safer anticancer treatment can be performed.

The administration route of the anticancer adjuvant may be administered through any general route as long as it can reach the target tissue. The anticancer adjuvant of the present invention may be administered intraperitoneally, intravenously, intramuscularly, subcutaneously, orally, intrapulmonary or rectal, depending on the purpose, but is not limited thereto. In addition, the anticancer adjuvant may be administered by any device capable of transporting an active substance to a target cell.

The anticancer adjuvant of the present invention may be preferably formulated as an anticancer adjuvant by including one or more pharmaceutically acceptable carriers in addition to the active ingredient for administration. Carriers, excipients or diluents that may be included in the anticancer adjuvant of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.

The anticancer adjuvant of the present invention may be a formulation for oral or parenteral administration, and the description of the formulation is substituted for the formulation of the pharmaceutical composition.

The present invention also includes any one or more selected from the group consisting of compounds represented by the following [Formula 1] or [Formula 2], pharmaceutically acceptable salts, precursors, hydrates, solvates, derivatives, and biological equivalents thereof It can provide a pharmaceutical composition for preventing or treating cancer or an anticancer adjuvant;

[Formula 1]

[Formula 2]

Wherein R is at least one selected from the group consisting of hydrogen, halogen, and C1 to C5 linear or branched alkyl, and n is an integer of 1 to 5. Preferably, R is hydrogen, and n is preferably 5.

According to a preferred embodiment of the present invention, the cancer is one or more cancers selected from the group consisting of colon cancer, lung cancer, stomach cancer, breast cancer, brain cancer, melanoma, prostate cancer, ovarian cancer, kidney cancer, pancreatic cancer and liver cancer. can

Hereinafter, the present invention will be described in more detail through examples. These examples are only for illustrating the present invention, and it will be apparent to those of ordinary skill in the art that the scope of the present invention is not to be construed as being limited by these examples.

cancer cell line and drug preparation

Whether the growth of several cancer cell lines is significantly inhibited when a malate aspartate shuttle (MAS) inhibitor and a carnitine acylcarnitine carrier (CAC) inhibitor are treated alone or in combination In order to confirm whether or not cancer cell lines exhibit a particularly significant synergistic effect among various cancer cell lines, several cancer cell lines and drugs to be treated were first prepared.

Specifically, the cancer cell lines are colon cancer (COLO 205 or HT29), melanoma (RPMI-8226, MALME-3M, UACC-62, M14, Lox or B16), lung cancer (H1975), gastric cancer (AGS), breast cancer (MDA) -MB-231), brain cancer (SF539 or U87), prostate cancer (PC3), ovarian cancer (OVCAR3), kidney cancer (ACHN or CAKI-1), liver cancer (HUH7) and pancreatic cancer (MIA PaCa-2, Capan-1) , Capan-2, SNU-324, SNU-213, BxPC-3, AsPC-1, SNU-410 or CFPAC1). Drugs are MAS inhibitors such as N-(1-Pyrenyl)maleimide, N-Phenylmaleimide, or N-phenyl maleamic acid. was prepared, and omeprazole as a CAC inhibitor was prepared at a concentration of 200 μM.

Comparison of N-(1-pyrenyl)maleimide and N-phenylmaleimide

N-(1-Pyrenyl)maleimide (N-(1-Pyrenyl)maleimide, KN-611), N-Phenylmaleimide (KN-612) and N-phenylmaleamic acid (N-phenyl) Maleamic acid, KN-613) was compared to evaluate better compounds as malate-aspartate shuttle (MAS) inhibitors.

<2-1> hERG K ⁺ channel binding assay-cardiotoxicity potential evaluation

The hERG tracer and memebrane fraction of the Predictor hERG fluorescence polarization assay kit (Life technology) were prepared by thawing at room temperature before use. Tracer and hERG assay buffer were diluted 1:62.5. KN-611, KN-612 or KN-613 (10 mM DMSO stock), astemizole (1 mM DMSO stock, Basal signal compensation), positive control (E-4031, 3 mM DMSO stock solution), negative control (DMSO) is diluted to a 4x solution of the final test concentration using assay buffer. Dispense 5 μl of each dilution solution into 384-well low volume flat bottom microplates (round; Corning). Dispense 10 μl of the membrane fraction into each well. 5 μl of hERG tracer is dispensed. Block the light and incubate at 25°C for 2 hours. Polarization is measured using a TECAN plate reader (Infinite M1000 pro Microplate Reader).

As a result, KN-611 showed an inhibition rate of less than 1% as shown in [Table 1] below, and was judged to be safe for cardiotoxicity caused by hERG K ⁺ CHANNEL binding.

process Concentration (μM) % inhibition positive control E-4031 10 94.9±0.674 experimental compound KN-611 10 less than 1%

As shown in [Fig. 3], KN-612 considered an IC50 value of 10 μM as a safety bottom line, and an IC50 value of 78 μM or higher was judged to be safe against induction of cardiac toxicity by hERG K ⁺ CHANNEL inhibition.

KN-613 considered an IC50 value of 10 μM as a safety bottom line, and an IC50 value of 683.916 μM, which was judged to be safe against induction of cardiac toxicity by hERG K ⁺ CHANNEL inhibition.

<2-2> CYP Cocktail inhibition assay

Dispense omeprazole (Omeprazole; Cat.# O104, Sigma-Aldrich; 10 mM in DMSO) and KN-611, KN-612 or KN-613 (10 mM DMSO stock) at each concentration in the library tubes. Pooled human liver microsomes (20 mg/ml; Cat# 452117, Corning) was added, mixed, and preincubated for 5 minutes in a shaking incubator set at 37°C. After 5 minutes, the cofactor NAPDH (Cat#451220, Cat#451200, Corning) is mixed and incubated in a shaking incubator for 20 minutes. After 20 minutes of reaction, acetonitrile containing a cold internal standard is added under ice environment to stop the reaction. After vortexing with a vortex mixer, the supernatant obtained by centrifugation (10,000 g, 4℃, 20 minutes) was injected into LC-MS/MS to measure the concentration of each metabolite by mass sepctrometry (Waters Xevo TQ-S) and Measure and quantify by Waters ACQUITY UPLC (UPLC). In general, if a compound at a concentration of 10 μM inhibits the activity of the CYP enzyme by 50% or more, it is predicted as a substance requiring attention to the activity of the CYP enzyme.

As a result, results such as the following [Table 2] to [Table 4] were obtained.

compound 1A2 2C9 2C19 2D6 3A4 KN-611 (10 μM) 97.4 72.6 24.6 40.6 99.1 inhibitor 87.2 92.3 92.5 92.9 99.6

compound 1A2 2C9 2C19 2D6 3A4 KN-612 (10 μM) 61.8 <1 <1 28.8 64.2 inhibitor 90.0 94.8 84.9 93.8 99.4

compound 1A2 2C9 2C19 2D6 3A4 KN-613 (10 μM) 7.7 8.6 8.8 5.4 5.5 inhibitor 91.5 95.5 93.4 93.9 99.5

<2-3> In vitro metabolic stability

Interspecies microsomes (20 mg/mL Rat liver microsomes (Cat# 452501, Corning) diluted with Potassium Phosphate buffer (0.5M, pH 7.4; Cat# 451201, Corning) in 96-well plates 20 mg/mL Mouse liver microsomes (Cat# 452701) , Corning) 20mg/mL Mixed Gender Pooled 150-donor Human liver microsomes (Cat# 452117, Corning)) was incubated at 37°C for 5 minutes. KN-611, KN-612 or KN-613 (10 mM DMSO stock) and NAPDH (Cat # 451220, Cat # 451200, Corning) are added and reacted at 37 ° C. for 30 minutes (KN-611, KN-612 or KN- Final concentration of 613: 1 μM, Microsome final concentration: 0.5 mg/ml). At that time, add cold acetonitrile containing internal standard to terminate the reaction. After centrifugation at 4000 rpm for 15 minutes, 100 μl of the supernatant was transferred to a 96-well plate and analyzed using mass sepctrometry (Agilent 6460) and HPLC (Agilent 1260) with LC-MS/MS. Verapamil and Buspirone are positive controls. According to the evaluation criteria for microsomal stability according to the % remaining value, which is the result of the reaction experiment for 30 minutes, >90% is considered a very stable compound with a half-life of 3 hours or more, and 70-90% is a relatively stable compound with a half-life of 1 hour to 3 hours. A compound < 30% was judged to be an unstable compound with a half-life of about 15 minutes.

As a result, as shown in [Table 5] to [Table 7], KN-611 and KN-613 could be evaluated as relatively stable compounds in humans, and KN-612 could be evaluated as very stable compounds.

compound (1 μM) human(%) mouse(%) KN-611 66.74 18.87 Buspirone 3.87 0.04

compound (1 μM) human(%) mouse(%) KN-612 >100 >100 Verapamil 22.7

compound (1 μM) human(%) mouse(%) KN-613 72 70 Buspirone 2 0.04

<2-4> SRB analysis

melanoma (MALME-3M, UACC-62, M14, Lox or B16), pancreatic cancer (MIA PaCa-2, Capan-1, Capan-2, SNU-324, SNU-213, BxPC-3 or AsPC-1) or Renal cancer (CAKI-1 or ACHN) cell lines (100 ml) were seeded into 96-well microtiter plates at plating densities ranging from 5000 to 20,000 cells/well depending on the doubling time of each cell line. After cell inoculation, microtiter plates were incubated for 24 h before addition of KN-611 or KN-612. 100 ml of KN-611 or KN-612 at a concentration of 0, 10, 20, 30, 40 or 50 μM was prepared and added to each well, and then the plate was incubated in a CO ₂ incubator. The assay was terminated by addition of cold TCA. Cells were fixed by gently adding 50 ml of cold 50% (w/v) TCA (final concentration: 10% TCA) and incubated at 4°C for 60 minutes. The supernatant was discarded, and the plate was washed 5 times with tap water and then air dried. A 0.4% (w/v) solution of Sulforhodamine B in 1% acetic acid (100 ml) was added to each well, and the plate was left at room temperature for 10 minutes. After staining, the plates were air dried after washing 5 times with 1% acetic acid to remove unbound dye. The bound dye was then solubilized with 10 mM trizma base and the absorbance was recorded at 515 nm using an automated plate reader.

As a result, as shown in [Fig. 4] and [Fig. 5], it was confirmed that KN-612 had a more significant cancer cell line proliferation inhibitory effect than KN-611.

<2-5> Preclinical xenograft tumor model

Balb/c-nu mice (OrientBio. Animal, Korea) were 6-8 weeks old before melanoma tumor induction. UACC62 cells (1×10 ⁷ ) were inoculated subcutaneously into mice using a 1 ml syringe, and after 2 weeks, the tumor volume was 130 mm ³ Upon reaching , the mice were divided into 4 groups: solvent control (5% DMSO, 10% Cremophor, 85% PBS), KN611 and KN612 groups. Vehicle alone or drug (KN-612 or KN-611; 20, 40 mg/kg) was orally administered once a day for 4 weeks, 5 days/week. Primary tumor sizes were measured every week using calipers. Tumor volume was calculated using the formula V = (A × B ² )/2, where V is the volume in mm ³ , A is the long diameter, and B is the short diameter. The method was reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) of the National Cancer Center Institute.

As a result, as shown in [Fig. 6], it was confirmed that KN-612 exhibited a more significant tumor suppressive effect than KN-611.

Cytotoxicity check

The cytotoxicity of N-phenylmaleimide (N-Phenyl maleimide, 20 μM) and/or omeprazole (200 μM) to normal cells was confirmed by SRB analysis and ATP level. Lung primary cell is lung, human uterine fibroblast is uterine, HEK293 is embryonic kidney, HaCaT is keratinocyte, and IMR90 is lung fibroblast.

As a result, as shown in [Fig. 7] and [Fig. 8], it was confirmed that N-phenylmaleimide and/or omeprazole did not show cytotoxicity to normal cells.

Confirmation of cancer cell line growth inhibitory effect according to MAS and/or CAC inhibition

In order to determine whether the growth is significantly inhibited when the cancer cell line is treated with a malate aspartate shuttle (MAS) inhibitor and/or a carnitine acylcarnitine carrier (CAC) inhibitor A sulforhodamine B assay was used.

<4-1> MAS inhibitor or CAC inhibitor alone

The purpose of this study was to determine the inhibitory effect of the MAS inhibitor or the CAC inhibitor alone on the proliferation of cancer cell lines by concentration. Specifically, pancreatic cancer cell lines or various cancer cell lines (kidney cancer, liver cancer, prostate cancer, breast cancer) of omeprazole, N-phenyl maleimide, or N-phenyl maleamic acid , colon cancer, stomach cancer, melanoma, ovarian cancer, or pancreatic cancer) was confirmed to have a proliferation inhibitory effect.

Specifically, several cancer cell lines (100 μl) prepared in <Example 1> were inoculated into a 96-well microplate in a density range of 5,000 to 20,000 cells/well depending on the doubling time, respectively. After that, each microplate was incubated for 24 hours prior to drug addition. A control medium (Contorl) was treated with a vehicle (0.1% DMSO) and then fixed by treatment with 50 μl 10% (w/v) TCA and cultured in a CO ₂ incubator at 4°C. Experimental group media for each drug were omeprazole 0, 10, 100 or 200 μM, N-phenylmaleimide 0, 10, 20, 30, 40 or 50 μM, N-phenylmaleamic acid 0, 10 μM, 100 μM, 500 μM, After treatment with 1mM, 2mM or 5mM in each well of a total of 100 μl, 48 hours later, 50 μl of 10% (w/v) TCA was treated and fixed, and then incubated in a CO ₂ incubator at 4° C. for 60 minutes. All media were washed 5 times with tap water and then dried in the air. Wells to which 0.4% (w/v) sulforhodamine B (SRB) solution (100 μl) was added to 1% acetic acid were stored at room temperature for 5 minutes. After staining with SRB, the plates were washed 5 times with 1% acetic acid to remove unbound dye, and then dried in air. The bound dyes were dissolved in 10 mM Tris base to determine the OD value at 515 nm. Cell proliferation was calculated as a percentage (%) by subtracting the measured value from the control plate value.

As a result, as shown in [Fig. 9] to [Fig. 11], omeprazole and N-phenylmaleimide inhibited the growth of the pancreatic cancer cell line in a concentration-dependent manner, and as shown in [Fig. 12], the concentration of N-phenylmaleimide was dependently inhibited the growth of various cancer cell lines.

<4-2> MAS inhibitor and CAC inhibitor combination

The purpose of this study was to determine the inhibitory effect of the MAS inhibitor or the CAC inhibitor alone on the proliferation of cancer cell lines by concentration. Specifically, omeprazole and N-phenyl maleimide (N-Phenyl maleimide), N- (1-prenyl) maleimide (N- (1-Pyrenyl) maleimide) or N-phenyl maleamic acid (N- The proliferation inhibitory effect of phenyl maleamic acid) on pancreatic cancer cell lines or various cancer cell lines was confirmed in the same manner as in Example <4-1> or the ATP generation inhibitory effect. Omeprazole was treated with 200 μM, N-phenylmaleimide was treated with 20, 25 or 30 μM, N-(1-prenyl)malimide was treated with 25 μM, and N-phenylmaleamic acid was treated with 1 or 2 mM.

As a result, as shown in [Fig. 13] to [Fig. 26], compared to the case of using omeprazole, N-phenylmaleimide, N-(1-prenyl)maleimide or N-phenylmaleamic acid alone, When omeprazole and N-phenylmaleimide, N-(1-prenyl)malimide, or N-phenylmaleamic acid were used in combination, the cancer cell line proliferation inhibitory effect and ATP production inhibitory effect were significantly increased.

MAS and/or CAC according to suppression cancer cell line Confirmation of growth inhibitory effect

If cancer cell lines are treated with a Malate Aspartate Shuttle (MAS) inhibitor and/or a Carnitine Acylcarnitine Carrier Shuttle (CAC) inhibitor, whether their growth is significantly inhibited in pancreatic cancer (MIA) PaCa-2), kidney cancer (ACHN/ATCC), melanoma (UACC62), liver cancer (SK-HEP-1), brain cancer (glioblastoma, U87)), stomach cancer (SNU-638), colorectal cancer (HCT-116) ) and ovarian cancer (OVCAR-8) tumor xenograft mouse models were prepared and confirmed.

Specifically, Balb/c-nu mice (OrientBio. Animal, Korea) were 6-8 weeks old before melanoma tumor induction. Each tumor cell (1×10 ⁷ ) was inoculated subcutaneously into mice using a 1 ml syringe, and after 2 weeks, the tumor volume was 130 mm ³ When reached, the mice were divided into 4 groups: solvent control (5% DMSO, 10% Cremophor, 85% PBS), omeprazole 75 mg/kg and/or N-phenylmaleimide (pancreatic cancer: 40 mg/kg, renal cancer; Melanoma, liver cancer, brain cancer, stomach cancer, colorectal cancer, ovarian cancer: 20 mg/kg). The vehicle alone or the drug was orally administered once a day, 5 days/week (pancreatic cancer, colon cancer: 7 weeks, kidney cancer, melanoma, liver cancer, brain cancer: 6 weeks, stomach cancer, ovarian cancer: 3 weeks). Primary tumor sizes were measured every week using calipers. Tumor volume was calculated using the formula V = (A × B ² )/2, where V is the volume in mm ³ , A is the long diameter, and B is the short diameter. The method was reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) of the National Cancer Center Institute.

As a result, the same results as [Fig. 27] to [Fig. 34] were obtained, and although omeprazole or N-phenylmaleimide alone showed a tumor suppressive effect on each carcinoma, omeprazole and N-phenylmaleimide were used in combination. In the case of treatment, it was confirmed that a synergistic effect occurred, indicating a significantly increased tumor suppression effect.

Claims (11)

As a malate-aspartate shuttle (Malate Aspartate Shuttle) inhibitor, a compound represented by the following [Formula 1], a compound represented by the following [Formula 2], or N-(1-pyrenyl)maleimide (N-(1) -Pyrenyl)maleimide); pharmaceutically acceptable salts thereof; hydrate; And any one or more selected from the group consisting of solvates and
Carnitine Acylcarnitine Carrier Shuttle inhibitors, including Omeprazole; pharmaceutically acceptable salts thereof; hydrate; And a pharmaceutical composition for preventing or treating cancer comprising any one or more selected from the group consisting of solvates:
[Formula 1]

[Formula 2]

Wherein R is any one or more selected from the group consisting of hydrogen, halogen and C1 to C5 straight-chain or branched alkyl,
Wherein n is 1 to 5.
delete delete The pharmaceutical composition for preventing or treating cancer according to claim 1, wherein the malic acid-aspartic acid reciprocal transport inhibitor and the carnitine acylcarnitine transporter transport inhibitor are included in a molar concentration ratio of 50:1 to 1:50.
The pharmaceutical composition for preventing or treating cancer according to claim 1, wherein the malic acid-aspartic acid transport inhibitor and the carnitine acylcarnitine transporter transport inhibitor are administered simultaneously or sequentially.
The pharmaceutical for preventing or treating cancer according to claim 5, wherein the malic acid-aspartic acid transport inhibitor and the carnitine acylcarnitine transporter transport inhibitor are administered in a mg/kg (mpk) ratio of 20:1 to 1:20. enemy composition.
The cancer according to claim 1, wherein the cancer is any one or more cancers selected from the group consisting of colon cancer, lung cancer, stomach cancer, breast cancer, brain cancer, melanoma, prostate cancer, ovarian cancer, kidney cancer, pancreatic cancer, and liver cancer. A pharmaceutical composition for prophylaxis or treatment.
As a malate-aspartate shuttle (Malate Aspartate Shuttle) inhibitor, a compound represented by the following [Formula 1], a compound represented by the following [Formula 2], or N-(1-pyrenyl)maleimide (N-(1) -Pyrenyl)maleimide); pharmaceutically acceptable salts thereof; hydrate; And any one or more selected from the group consisting of solvates and
Carnitine Acylcarnitine Carrier Shuttle inhibitors, including Omeprazole; pharmaceutically acceptable salts thereof; hydrate; And an anticancer adjuvant comprising at least one selected from the group consisting of solvates:
[Formula 1]

[Formula 2]

Wherein R is any one or more selected from the group consisting of hydrogen, halogen and C1 to C5 straight-chain or branched alkyl,
Wherein n is 1 to 5. delete delete delete

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