KR102674206B1 - Novel compounds as Transglutaminase 2 inhibitors and uses thereof - Google Patents

Abstract

The present invention relates to a novel compound and a pharmaceutical composition containing the same for the treatment or prevention of transglutaminase-2 related diseases.
The compound of formula 1 according to the present invention can significantly inhibit the activity of transglutaminase-2, and can prevent kidney disease, cancer, and kidney disease that may be caused by increased activity of transglutaminase-2. It can be used as an active ingredient in compositions for preventing, improving, or treating various diseases such as:

Description

Novel compounds as Transglutaminase 2 inhibitors and uses thereof}

The present invention relates to a novel compound for inhibiting transglutaminase-2 activity and a composition containing the same for preventing or treating cancer.

Transglutaminase (TGase; TG) is an enzyme that catalyzes the bond between the γ-carboxamide group of a glutamine residue bound to a specific peptide and various amines, and free amine groups (e.g., protein- or peptide-bound Lysine) is an enzyme that specifically catalyzes the formation of a covalent bond between the ε-amino group of lysine and the γ-carboxamide group of protein or peptide-bound glutamine. Among these, type 2 TGase (TGase2; TG2) was initially thought to play a major role in preventing damage and promoting defense and recovery, but recent studies have shown that when abnormally excessively induced, it can cause nerve damage. It is reported to play a major role in the development of diseases such as neurodegenerative diseases, atherosclerosis, inflammatory diseases, and autoimmune diseases. In addition, it irreversibly binds to matrix proteins such as collagen, fibronectin, laminia, nidogen, and proteoglycan, or proteolytic enzymes of the extracellular matrix ( It is suggested that it increases resistance to proteolytic enzymes, induces severe extracellular matrix deposition, and participates in tissue fibrosis. In fact, it has been reported that TG2 plays a major role in experimental kidney and liver fibrosis, and that when its activity is inhibited using an inhibitor, the degree of fibrosis is reduced. TG2 is closely related to TGF (transforming growth factor)-β1, which is a major mediator in collagen synthesis and increased epithelial-mesenchymal transition, and is a major factor in activating TGF-β1 in an inactive state. As TGF-β1 is reported to be a major inducer of TG2, it is believed that TGF-β1 and TG2 play a close role in the process of tissue fibrosis.

Accordingly, research on safe and effective transglutaminase-2 inhibitors is required to develop new drugs to treat diseases caused by abnormal transglutaminase-2 expression, but the research is still minimal.

Republic of Korea Patent Publication No. 10-2016-0053871 (Title of the invention: Pharmaceutical composition for treating or preventing diseases related to transglutaminase 2 containing streptonigrin and use thereof, Applicant: MD Biolab Co., Ltd., Publication date: May 13, 2016) Republic of Korea Patent No. 10-1267580 (Title of Invention: Transglutaminase 2 as a kidney cancer diagnostic marker and its use for kidney cancer diagnosis, Applicant: National Cancer Center, Registration date: May 20, 2013) Republic of Korea Patent Publication No. 10-2020-0096141 (Title of the invention: Pharmaceutical composition for preventing or treating colorectal cancer containing streptonigrin and an anticancer agent, Applicant: MD Biolab Co., Ltd., Publication date: August 11, 2020) Republic of Korea Patent No. 10-2147721 (Title of Invention: Pharmaceutical composition for preventing or treating cancer containing streptonigreen and rapamycin as active ingredients, Applicant: MD Biolab Co., Ltd., Registration date: August 19, 2020 Day) Republic of Korea Patent Publication No. 10-2020-0094110 (Title of the invention: Pharmaceutical composition for preventing or treating brain tumors containing streptonigrin and anticancer drugs, Applicant: MD Biolab Co., Ltd., Publication date: August 6, 2020)

The purpose of the present invention is to provide a novel compound for inhibiting transglutaminase-2 activity or a pharmaceutically acceptable salt thereof and a composition for preventing or treating cancer containing the same.

According to one aspect of the present invention, a novel compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof is provided.

[Formula 1]

In Formula 1, R ₁ or R ₂ are independently hydrogen, halogen, or trifluoromethyl, excluding cases where they are all hydrogen. More preferably, in Formula 1, R ₁ or R ₂ is independently hydrogen, halogen, or trifluoromethyl, and trifluoromethyl is necessarily included among R ₁ and R ₂ .

The halogen is selected from F, Cl, Br or I.

As a specific example of the compound represented by Formula 1 of the present invention, it may be selectively included from the following 5 types of compounds.

The compound of Formula 1 according to the present invention can be used in the form of a pharmaceutically acceptable salt. The term “pharmaceutically acceptable salt” refers to a compound salt that retains the pharmacological activity of the parent compound, such as (i) salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; (ii) Acetic acid, propionic acid, isobutyric acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, and benzoic acid. , salts formed with organic acids such as hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid; (iii) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion, an alkaline earth metal ion, or an aluminum ion; (iv) Coordinates with organic bases such as ethanolamine, diethanolamine, triethanolamine, and N-methylglucamine; or (v) a salt of an amino acid such as alginate.

According to another aspect of the present invention, a transglutaminase-2 activity inhibitor containing the compound represented by the above-mentioned formula (1) or a pharmaceutically acceptable salt thereof is provided.

According to another aspect of the present invention, a pharmaceutical composition for preventing or treating diseases caused by increased transglutaminase-2 activity, containing the compound represented by the above-mentioned formula (1) or a pharmaceutically acceptable salt thereof. This is provided.

“Disease caused by increased transglutaminase 2 activity” of the present invention includes all diseases caused by increased activity, such as overexpression of transglutaminase 2, and specifically includes neurological diseases and cancer. Includes.

In the case of neurological diseases, they are diseases related to the death or damage of nerve cells, especially Alzheimer's disease, multi-infarct dementia, mixed type of Alzheimer's disease and multi-infarct dementia, Parkinson's disease, hypothyroidism, alcoholic dementia, Alzheimer's disease, Huntington's disease, etc. A representative example is central nervous system disease caused by damage and death of central nervous system cells.

In the case of cancer, colon cancer, small intestine cancer, rectal cancer, anal cancer, esophageal cancer, pancreatic cancer, stomach cancer, kidney cancer, uterine cancer, breast cancer, lung cancer, lymph node cancer, thyroid cancer, prostate cancer, leukemia, skin cancer, colon cancer, brain tumor, bladder cancer, and ovarian cancer. , gallbladder cancer, etc., and preferably includes kidney cancer, but is not limited thereto. The kidney cancer includes clear cell RCC, papillary RCC, chromophobe RCC, collecting tube RCC, and urothelial cancer (transitional cancer). It is characterized by being selected from the group consisting of cell carcinoma (TCC), but is not limited thereto.

The pharmaceutical composition of the present invention may contain the compound of Formula 1 in the form of a pharmaceutically acceptable salt. The “pharmaceutically acceptable salt” is as defined above.

Additionally, the pharmaceutical composition of the present invention may contain an isomer, solvate, or prodrug of the compound of Formula 1 of the present invention. “Isomers” herein include all possible stereochemical isomers, including diastereomers and enantiomers. The compounds of the present invention are understood to refer to a mixture of all possible stereochemical isomeric forms. Additionally, the term “solvate” refers to a complex of a solute (e.g., a compound of Formula 1) and a solvent, and when the solvent is water, the solvate may be referred to as a hydrate. The term “prodrug” refers to a compound that is converted into an active compound with medicinal properties through bioabsorption and metabolism after being administered in vivo. The prodrug is a compound that is itself inert or less active than the active compound, but may provide advantageous properties for handling, administration, or metabolism. The prodrug may be in the form of an ester of the active compound (e.g., a physiologically acceptable metabolically labile ester), a sugar derivative, or an amino acid ester derivative.

The pharmaceutical composition of the present invention may further include a pharmaceutically acceptable carrier in addition to the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof. The pharmaceutically acceptable carrier may be one commonly used in the pharmaceutical field, and may be an excipient (e.g., starch, calcium carbonate, sucrose, lactose, sorbitol, mannitol, cellulose, etc.) or a diluent (e.g., physiological saline solution, purified water, etc.).

Additionally, if necessary, the pharmaceutical composition of the present invention may contain pharmaceutically acceptable additives other than the pharmaceutically acceptable carrier, such as binders, disintegrants, lubricants, peeling agents, film coating bases, and enteric films. It may further include a coating base, a soft capsule base, a solubilizing agent, an emulsifier, a suspending agent, a stabilizer, a buffer, an antioxidant, a surfactant, a sweetener, a flavoring agent, a preservative, a thickener, a flavoring agent, or a coloring agent.

The pharmaceutical composition of the present invention can be administered orally or parenterally. In the case of parenteral administration, it can be administered by intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, endothelial administration, topical administration, intranasal administration, intrapulmonary administration, and intrarectal administration. For oral administration, the composition of the present invention may be formulated in the form of a solid or liquid dosage form. Solid dosage forms may be, for example, tablets, capsules (soft & hard capsules), powders, granules, pills, troches, etc., and liquid dosage forms may be, for example, elixirs, suspensions, emulsions, solutions, syrups, etc. , rimonadese, etc.

The dosage of the pharmaceutical composition of the present invention can be determined considering the administration method, the age and gender of the recipient, the patient's severity, condition, inactivation rate, and concomitant drugs, and can be administered once or in several divided doses.

The present invention relates to a novel compound for inhibiting transglutaminase-2 activity or a pharmaceutically acceptable salt thereof and a composition for preventing or treating cancer containing the same, wherein the compound of formula 1 is transglutaminase-2. It significantly inhibits the activity of It can be used as an active ingredient in a composition for improvement or treatment.

Hereinafter, preferred embodiments of the present invention will be described in detail. However, the present invention is not limited to the embodiments described herein and may be embodied in other forms. Rather, it is provided to ensure that the content introduced here is thorough and complete, and to sufficiently convey the spirit of the present invention to those skilled in the art.

The compounds of the present invention can be prepared, for example, according to [Scheme 1] below:

[Scheme 1]

Functional group R ₁ R ₂ a C F ₃ F b F C F ₃ c C F ₃ H d H C F ₃ e Br CF ₃

The conditions in Scheme 1 are as follows: (a) HNO ₃ , 0°C, room temperature (RT), 100°C; (b) Pd/C, H ₂ , Methanol, RT, 24hr; (c) Toluene, Reflux, 6hr; (d) HNO ₃ , HCl, 80°C, RT

Scheme 1 shows a method for synthesizing benzimidazole derivatives, and benzimidazole derivative compounds 5a-e are synthesized using 1,4-dimethoxybenzene as a starting material using the synthetic process as disclosed in Scheme 1. possible. For example, 1,4-dimethoxybenzene (1) is nitrated using HNO3 to prepare compound (2), and reduction reaction is performed using H2 under a Pd/c catalyst. Compound (3) is prepared by reducing the nitro group to an amine group. The synthesis of the benzimidazole ring is achieved by reacting the 1,2-diamine group of compound (3) with a suitable aldehyde material and cyclization under reflux conditions. Finally, compounds (4a-e) are subjected to demethylation and chlorination in the presence of HNO ₃ and HCl to prepare final target substances (5a-e).

Hereinafter, to aid understanding of the present invention, examples are presented with representative compounds of the present invention. However, the following examples are provided only to make the present invention easier to understand, and the content of the present invention is not limited by the following examples.

<Example 1: Preparation of intermediate compound>

Example 1-1: Preparation of 1,4-dimethoxy-2,3-dinitrobenzene intermediate (Compound 2)

15 mL of nitric acid was added to 5 g (36.19 mmol) of compound 1,4-dimethoxybenzene and stirred for 1 hour at 0°C, 1 hour at room temperature, and 1 hour at 100°C. After cooling to room temperature, the mixture is neutralized with 1N NaOH solution at 0°C and filtered under reduced pressure to obtain a solid compound. Compound 2, the following intermediate, was prepared by performing silica gel column chromatography (developing solvent: n-hexanes/ethyl acetate = 4:1).

Yield: 79%;

¹ H NMR (CDCl ₃ ) δ 3.93(6H, CH ₃ ), 7.21(2H, CH)

MS (ESI): m/z = 228.68 (M ⁺ +1)

Example 1-2: Preparation of 3,6-dimethoxybenzene-1,2-diamine intermediate (Compound 3)

Dissolve 2 g (8.76 mmol) of the 1,4-dimethoxy-2,3-dinitrobenzene intermediate prepared above in 10 mL methanol and add 100 mg of Pd/C catalyst. The interior was replaced with hydrogen gas and stirred at room temperature for 24hr. The mixture was filtered under reduced pressure, the resulting filtrate was concentrated under reduced pressure, and subjected to silica gel column chromatography (developing solvent: n-hexanes/ethyl acetate = 4:1) to prepare the following intermediate, Compound 3.

Yield: 85%;

¹ H NMR (CDCl ₃ ) δ 3.51(4H, s, NH ₂ ), 6.31(2H, s, CH), 3.81(6H, s, CH ₃ )

MS (ESI): m/z = 168.73 (M ⁺ +1)

<Example 2: Preparation of 4,7-dimethoxy-1H-benzoimidazole intermediate (compounds 4a-e)>

1 g (5.94 mmol) of the 3,6-dimethoxybenzene-1,2-diamine intermediate prepared above was dissolved in 15 mL toluene and dissolved in 3-fluoro-4-(trifluoromethyl)benzaldehyde, 4-fluoro-3-(trifluoromethyl)benzaldehyde. , 11.88 mmol each of 4-(trifluoromethyl)benzaldehyde, 3-(trifluoromethyl)benzaldehyde, and 4-bromo-3-(trifluoromethyl)benzaldehyde were added and refluxed for 6 hours. After cooling to room temperature, extraction was performed with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. After adding ethyl ether, the mixture was filtered under reduced pressure to prepare the following intermediates, Compounds 4a to 4e, which are solid compounds.

Example 2-1: 2-(3-fluoro-4-(trifluoromethyl)phenyl)-4,7-dimethoxy-1H-benzo[d]imidazole (Compound 4a)

Yield: 78%

^1H NMR (CDCl ₃ ) δ 4.21(1H, NH), 8.32(1H, CH), 7.65(1H, CH), 7.25(1H, CH), 6.79(2H, CH), 3.81(6H, CH ₃ )

MS (ESI): m/z = 340.11 (M ⁺ +1)

Example 2-2: 2-(4-fluoro-3-(trifluoromethyl)phenyl)-4,7-dimethoxy-1H-benzo[d]imidazole (Compound 4b)

Yield: 81%

^1H NMR (CDCl ₃ ) δ 5.24(1H, NH), 8.12(1H, CH), 7.74(1H, CH), 7.25(1H, CH), 6.85(2H, CH), 3.86(6H, CH ₃ )

MS (ESI): m/z = 340.03 (M ⁺ +1)

Example 2-3: 4,7-dimethoxy-2-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole (Compound 4c)

Yield: 82%

¹ H NMR (CDCl ₃ ) δ 4.53 (1H, NH), 8.54 (2H, CH), 7.64 (2H, CH), 6.83 (2H, CH), 3.82 (6H, CH ₃ )

MS (ESI): m/z = 322.12 (M ⁺ +1)

Example 2-4: 4,7-dimethoxy-2-(3-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole (Compound 4d)

Yield: 77%

^1H NMR (CDCl ₃ ) δ 4.13(1H, NH), 3.81(6H, CH ₃ ), 8.63(1H, CH), 8.25(1H, CH), 7.56(1H, CH), 7.42(1H, CH) , 6.83(2H, CH)

MS (ESI): m/z = 322.12 (M ⁺ +1)

Example 2-5: 2-(4-bromo-3-(trifluoromethyl)phenyl)-4,7-dimethoxy-1H-benzo[d]imidazole (Compound 4e)

Yield: 81%

¹ H NMR (CDCl ₃ ) δ 4.83 (1H, NH), 8.05 (1H, CH), 7.65 (1H, CH), 7.54 (1H, CH), 6.83 (2H, CH), 3.81 (6H, CH ₃ )

MS (ESI): m/z = 400.23 (M ⁺ +1)

<Example 3: Preparation of compounds 5a-e>

9 mL of hydrochloric acid and 3 mL of nitric acid were slowly added to 2.00 mmol of each intermediate prepared in Example 2, and the mixture was stirred at 80°C for 1 hour and at room temperature for 1 hour. The mixture was neutralized with sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. After adding ethyl ether, the mixture was filtered under reduced pressure to prepare the following compounds in solid form.

Example 3-1: 5,6-dichloro-2-(3-fluoro-4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-4,7-dione (Compound 5a)

Yield: 82%

^1H NMR (CDCl ₃ ) δ 13.13(1H, NH), 8.32(1H, CH), 7.64(1H, CH), 7.42(1H, CH)

MS (ESI): m/z = 377.87 (M ⁺ +1)

Example 3-2: 5,6-dichloro-2-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-4,7-dione (Compound 5b)

Yield: 85%

^1H NMR (CDCl ₃ ) δ 13.62(1H, NH), 8.12(1H, CH), 7.75(1H, CH), 7.22(1H, CH)

MS (ESI): m/z = 377.81 (M ⁺ +1)

Example 3-3: 5,6-dichloro-2-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-4,7-dione (Compound 5c)

Yield: 81%

^1H NMR (CDCl ₃ ) δ 13.42(1H, NH), 8.53(2H, CH), 7.62(2H, CH)

MS (ESI): m/z = 359.82 (M ⁺ +1)

Example 3-4: 5,6-dichloro-2-(3-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-4,7-dione (Compound 5d)

Yield: 89%

^1H NMR (CDCl ₃ ) δ 12.92(1H, NH), 8.62(1H, CH), 8.22(1H, CH), 7.54(1H, CH), 7.42(1H, CH)

MS (ESI): m/z = 359.89 (M ⁺ +1)

Example 3-5: 2-(4-bromo-3-(trifluoromethyl)phenyl)-5,6-dichloro-1H-benzo[d]imidazole-4,7-dione (Compound 5e)

Yield: 86%

¹ H NMR (CDCl ₃ ) δ 13.22 (1H, NH), 8.05 (1H, CH), 7.67-7.61 (2H, CH)

MS (ESI): m/z = 439.75 (M ⁺ +1)

<Experimental Example 1: in vitro Transglutaminase 2 Assay>

The incorporation of [1,4-14C] putrescine into succinylated casein was measured to determine the effect of each compound on transglutaminase 2 (TGase 2) activity. The inhibitory effect was determined. Pre-incubate 1 mU of TGase 2 from guinea pig liver (Sigma, St. Louis, MO, USA) with various concentrations of GK13 or GK921 prepared in 0.1 mL reaction buffer with or without 10 mM CaCl ₂ for 10 minutes. (preincubation), and 0.4 mL of substrate solution containing 2% succinylated casein and 100 nCi of [1,4-14C] putrescine was added. After incubation at 37°C for 1 hour, the reaction was terminated by adding 4 mL of cold (4°C) 7.5% (w/v) trichloroacetic acid (TCA). The TCA-insoluble precipitate was recovered on a GF/A-grade glass filter (Millipore, Billerica, MA, USA), washed with cold 5% (w/v) TCA, dried, and counted in a scintillation counter. The binding of the radiolabel was evaluated using Beckman Coulter, Brea, CA, USA). TGase 2 pre-incubated with buffer only was used as a positive control. Scintillation counts were compared with those of the positive control group, and the IC ₅₀ value of each compound was determined using the logistic linear regression method. Data are expressed as the average of three independent experiments.

compound TG2 activity (IC ₅₀ , μM) 5a 0.635 5b 0.429 5c 0.500 5d 0.768 5e 0.476

As shown in Table 2, all compounds prepared in the present invention were confirmed to have an IC ₅₀ (The half maximal inhibitory concentration) in nM units, confirming that they exhibit an inhibitory effect on TGase2 enzyme activity.

<Experimental Example 2: SRB (Sulforhodamine B) Assay>

ACHN and CAKI-1 cells (10,000 cells/well concentration, 100 μL) were cultured individually in 96-well microtiter plates. After 24 hours, drug (100 μL) was added to each well, and the cultures were further incubated at 37°C for 48 hours. The cells were then fixed in TCA (50 μL per well). The plates were incubated at 4°C for a minimum of 1 hour or a maximum of 3 hours. The liquid was removed from the plate, washed five times with water and left to dry at room temperature (RT) for about 12 to 24 hours. The fixed cells were stained with 100 μL SRB for 5 minutes at room temperature. After staining, the plates were washed three times with 1% glacial acetic acid and dried at room temperature for about 12 to 24 hours. Afterwards, SRB was dissolved in 10 mM Trizma base, and absorbance was measured at 515 nm. The effect of the drug was expressed as GI ₅₀ (50% growth inhibition).

Specifically, compounds 5a to 5e were tested at a concentration of 10 ^-9 , 10 ^-8 , 10 ^-7 , 10 ^-6 , and 10 ^-5 M, respectively, using ACHN and CAKI-1 cancer cell groups, The percentage reduction of control values of SRB was measured.

compound SRB (GC ₅₀ , μM) ACHN CAKI-1 5a 2.42 3.00 5b 2.10 2.76 5c 2.06 2.75 5d 2.17 3.27 5e 3.27 3.37

As shown in Table 3, all five compounds showed excellent GI ₅₀ values, confirming that they have excellent anticancer effects.

The description of the present invention described above is for illustrative purposes, and those skilled in the art will understand that the present invention can be easily modified into other specific forms without changing the technical idea or essential features of the present invention. will be. Therefore, the embodiments described above should be understood in all respects as illustrative and not restrictive.

Claims (9)

A new compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
[Formula 1]

In Formula 1, R ₁ or R ₂ is independently hydrogen, halogen, or trifluoromethyl,
The halogen is selected from F, Cl, Br or I,
Except for the case where R ₁ and R ₂ are both hydrogen,
Excluding cases where R ₁ is Br and R ₂ is hydrogen,
Excluding the case where R ₁ is Br and R ₂ is F. delete According to paragraph 1,
The compound represented by Formula 1 is a compound or a pharmaceutically acceptable salt thereof, characterized in that it is selected from the following five types of compounds.
A pharmaceutical for the prevention or treatment of nervous system diseases, characterized in that it contains the compound according to any one of claims 1 and 3 or a pharmaceutically acceptable salt thereof and has the effect of inhibiting transglutaminase-2 activity. Composition. According to clause 4,
The neurological disease is for the prevention or treatment of neurological diseases, characterized in that they are selected from the group consisting of Alzheimer's disease, multi-infarct dementia, a combination of Alzheimer's disease and multi-infarct dementia, Parkinson's disease, hypothyroidism, alcoholic dementia, Alzheimer's disease, and Huntington's disease. Pharmaceutical composition. A pharmaceutical composition for the prevention or treatment of cancer, characterized in that it contains the compound according to any one of claims 1 and 3 or a pharmaceutically acceptable salt thereof and has the effect of inhibiting transglutaminase-2 activity. . delete According to clause 6,
The above cancers include colon cancer, small intestine cancer, rectal cancer, anal cancer, esophageal cancer, pancreatic cancer, stomach cancer, kidney cancer, uterine cancer, breast cancer, lung cancer, lymph node cancer, thyroid cancer, prostate cancer, leukemia, skin cancer, colon cancer, brain tumor, bladder cancer, ovarian cancer, and A pharmaceutical composition for preventing or treating cancer, characterized in that it is selected from the group consisting of gallbladder cancer. According to clause 8,
The kidney cancer includes clear cell RCC, papillary RCC, chromophobe RCC, collecting tube RCC, and urothelial cancer (transitional cancer). A pharmaceutical composition for preventing or treating cancer, characterized in that it is selected from the group consisting of cell carcinoma (TCC).