KR20220129446A - 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. Since a compound of chemical formula 1 according to the present invention can significantly inhibit the activity of transglutaminase-2, it is possible to be used as an active component of a composition for preventing, alleviating or treating various diseases such as kidney disease and cancer, which can be caused by increased activity of transglutaminase-2.

Description

Novel compounds as Transglutaminase 2 inhibitors and uses thereof {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 for preventing or treating cancer containing the same.

Transglutaminase (TGase; TG) is an enzyme that promotes binding between the γ-carboxamide group of a glutamine residue bound to a specific peptide and various amines, and a free amine group (e.g., protein or peptide-binding Lysine), in particular, is an enzyme that promotes 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 them, type 2 TGase (TGase2; TG2) was primarily considered to play a major role in promoting injury prevention, defense, and repair. 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 extracellular matrix proteolytic enzymes ( It has been suggested that it is involved in tissue fibrosis by increasing resistance to proteolytic enzymes, inducing severe extracellular matrix deposition. In fact, it has been reported that TG2 plays a major role in experimental renal and liver fibrosis, and when its activity is inhibited using an inhibitor, the degree of fibrosis is reduced. TG2 is closely related to transforming growth factor (TGF)-β1, which is a major mediator in the increase of collagen synthesis and epithelial-mesenchymal transition. It has been reported that TGF-β1 is a major inducer of TG2, suggesting that TGF-β1 and TG2 have a close function in the tissue fibrosis process.

Accordingly, research on safe and effective transglutaminase-2 inhibitors is required for the development of new drugs for treating diseases caused by abnormal transglutaminase-2 expression, but the situation is still insignificant.

Korean Patent Laid-Open Patent No. 10-2016-0053871 (Title of the Invention: Pharmaceutical composition for treatment or prevention of transglutaminase 2 related disease including streptonigrin and use thereof, Applicant: MD Biolab Co., Ltd., publication date: May 13, 2016) Republic of Korea Patent Registration No. 10-1267580 (Title of the invention: Transglutaminase 2 as a kidney cancer diagnostic marker and use of the same 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 comprising streptonigreen and anticancer agent, Applicant: MD Biolab Co., Ltd., publication date: August 11, 2020) Republic of Korea Patent Registration No. 10-2147721 (Title of the invention: Pharmaceutical composition for preventing or treating cancer comprising streptonigreen and rapamycin as active ingredients, Applicant: MD Biolab Co., Ltd., Registration date: August 19, 2020 Work) Republic of Korea Patent Publication No. 10-2020-0094110 (Title of the invention: a pharmaceutical composition for preventing or treating brain tumors comprising streptonigrin and an anticancer agent, Applicant: MD Biolab Co., Ltd., publication date: August 06, 2020)

An object 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, there is provided a novel 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, except when all of them are 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 in the following five compound groups.

The compound of Formula 1 according to the present invention may be used in the form of a pharmaceutically acceptable salt. The "pharmaceutically acceptable salt" refers to a compound salt that retains the pharmacological activity of the parent compound, for example, (i) a salt formed with an inorganic acid 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, 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 acidic protons present in the parent compound are replaced by metal ions, such as alkali metal ions, alkaline earth metal ions, or aluminum ions; (iv) coordination with organic bases such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine; or (v) a salt of an amino acid such as alginate.

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

According to another aspect of the present invention, a pharmaceutical composition for preventing or treating a disease caused by an increase in transglutaminase-2 activity containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof. this is provided

The "disease caused by increased transglutaminase 2 activity" of the present invention includes all diseases caused by increased transglutaminase 2 activity, such as overexpression, specifically, neurological diseases and cancer. include

Neurological diseases are diseases related to the death or damage of nerve cells, especially Alzheimer's disease, multi-infarct dementia, a mixed type of Alzheimer's disease and multi-infarct dementia, Parkinson's disease, hypothyroidism, alcoholic dementia, Alzheimer's disease, Huntington's disease, etc. Central nervous system diseases caused by damage and death of central nervous system cells are representative.

In the case of cancer, colorectal cancer, small intestine cancer, rectal cancer, anal cancer, esophageal cancer, pancreatic cancer, stomach cancer, kidney cancer, uterine cancer, breast cancer, lung cancer, lymph gland cancer, thyroid cancer, prostate cancer, leukemia, skin cancer, colon cancer, brain tumor, bladder cancer, ovarian cancer , gallbladder cancer, and the like, and preferably kidney cancer, but is not limited thereto. The kidney cancer is clear cell RCC, papillary RCC, chromophobe RCC, collecting tube RCC, and urothelial cancer, transitional It is characterized in that it is 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.

In addition, the pharmaceutical composition of the present invention may contain an isomer, solvate, or prodrug of the compound of Formula 1 of the present invention. "Isomer" herein includes all possible stereochemically isomers, including diastereomers and enantiomers. It can be understood that the compounds of the present invention refer to mixtures of all possible stereochemically isomeric forms. In addition, the term "solvate" refers to a complex of a solute (eg, 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 having a medicinal effect by bioabsorption and metabolism after administration in vivo. The prodrug is a compound that is itself inactive or less active than the active compound, provided that it may provide advantageous properties for handling, administration, or metabolism. The prodrug may be in the form of an ester of the active compound (eg, 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 an excipient (eg, starch, calcium carbonate, sucrose, lactose, sorbitol, mannitol, cellulose, etc.) or a diluent (eg, physiological saline, purified water, etc.).

In addition, if necessary, the pharmaceutical composition of the present invention may contain pharmaceutically acceptable additives other than the pharmaceutically acceptable carrier, for example, a binder, a disintegrant, a lubricant, a coating agent, a film coating base, an enteric film. 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 sweetening agent, a flavoring agent, a preservative, a thickening agent, a flavoring agent, or a coloring agent.

The pharmaceutical composition of the present invention may be administered orally or parenterally. In the case of parenteral administration, intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, endothelial administration, topical administration, intranasal administration, intrapulmonary administration, and rectal administration may be used. 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 can be, for example, tablets, capsules (soft & hard capsules), powders, granules, pills, troches, and the like, and liquid dosage forms can be, for example, elixirs, suspensions, emulsions, solutions, syrups, etc. , and may be in the form of limonaadese.

The dosage of the pharmaceutical composition of the present invention may be determined in consideration of the administration method, the age, sex, the severity of the patient, the condition, the inactivation rate, and the drug used in combination, and may be administered once or divided into several 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 significantly inhibits the activity of, and has excellent apoptosis effect on cancer cells, prevention of various diseases, particularly various cancer diseases, including kidney disease, which may be caused by increased activity of transglutaminase-2; It can be used as an active ingredient of 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 so that this disclosure will be thorough and complete, and will fully convey the spirit of the invention to those skilled in the art.

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

[Scheme 1]

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

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

Scheme 1 shows a method for synthesizing benzoimidazole derivatives. Benzoimidazole derivative compounds 5a-e are synthesized using 1,4-dimethoxybenzene as a starting material using the synthesis process as described in Scheme 1. It is 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. to reduce the nitro group to an amine group to prepare compound (3). The synthesis of a benzimidazole ring is achieved through cyclization under reflux conditions by reacting the 1,2-diamine group of compound (3) with a suitable aldehyde material. Finally, compounds (4a-e) are subjected to demethylation and chlorination in the presence of HNO ₃ and HCl to prepare a final target material (5a-e).

Hereinafter, examples are given by giving representative compounds of the present invention in order to help the understanding of the present invention. However, the following examples are only provided for easier understanding of the present invention, and the contents of the present invention are 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)

To 5 g (36.19 mmol) compound 1,4-dimethoxybenzene, 15 mL of nitric acid was added and stirred at 0° C. for 1 hour, at room temperature for 1 hour, and at 100° C. for 1 hour. 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. By performing silica gel column chromatography (eluent: n-hexanes/ethyl acetate = 4:1), the following intermediate compound 2 was prepared.

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)

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

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 (Compound 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 3-fluoro-4-(trifluoromethyl)benzaldehyde, 4-fluoro-3-(trifluoromethyl)benzaldehyde , 4-(trifluoromethyl)benzaldehyde, 3-(trifluoromethyl)benzaldehyde, and 4-bromo-3-(trifluoromethyl)benzaldehyde were added at 11.88 mmol each, followed by reflux reaction 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%

¹ H 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%

¹ H 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%

¹ H 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 compound 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 hydrogen carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. After addition of ethyl ether, it was filtered under reduced pressure to prepare the following compounds, which are solid compounds.

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

Yield: 82%

¹ H 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%

¹ H 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%

¹ H 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%

¹ H 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>

By measuring the binding (incorporation) of [1,4-14C] putrescine to succinylated casein (succinylated casein), transglutaminase 2 (TGase 2) of each compound for activity The inhibitory effect was determined. 1 mU of guinea pig liver-derived TGase 2 (Sigma, St. Louis, MO, USA) was pre-incubated with various concentrations of GK13 or GK921 in 0.1 mL reaction buffer with or without 10 mM CaCl ₂ for 10 min. After preincubation, 0.4 mL of a substrate solution containing 2% succinylated casein and 100 nCi of [1,4-14C] putrescine was added. After incubation at 37° C. for 1 hour, 4 mL of cold (4° C.) 7.5% (w/v) trichloroacetic acid (TCA) was added to terminate the reaction. The TCA-insoluble precipitate was recovered with a GF/A-grade glass filter (Millipore, Billerica, MA, USA), washed with cold 5% (w/v) TCA, dried, and scintillated by a scintillation counter. Beckman Coulter, Brea, CA, USA) was used to evaluate the binding of the radiolabel. TGase 2 pre-incubated with buffer only was used as a positive control. The scintillation counts were compared with that of the positive control group, and the IC ₅₀ value of each compound was determined using a logistic linear regression method. Data are presented 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 the compounds prepared in the present invention were confirmed to have an IC ₅₀ (The half maximal inhibitory concentration) of nM unit, thereby 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 each individually cultured in 96-well microtiter plates. After 24 h, drug (100 μL) was added to each well and the culture was further incubated at 37° C. for 48 h. 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 with water 5 times and then left to dry at room temperature (RT) for about 12 to 24 hours. The fixed cells were stained with 100 μL SRB for 5 min at room temperature. After staining, the plates were washed 3 times with 1% glacial acetic acid and dried at room temperature for about 12 to 24 hours. Then, 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, the compounds of compounds 5a to 5e were tested at concentrations of 10 ^-9 , 10 ^-8 , 10 ^-7 , 10 ^-6 , and 10 ^-5 M, respectively, using ACHN and CAKI-1 cell cancer cell groups, The percentage reduction in the control value of SRB was determined.

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 disclosed in Table 3, all of the five compounds exhibited excellent GI ₅₀ values, thereby confirming excellent anticancer effects.

The above description of the present invention is for illustration, and those of ordinary skill in the art to which the present invention pertains can understand that it can be easily modified into other specific forms without changing the technical spirit or essential features of the present invention. will be. Therefore, it should be understood that the embodiments described above are illustrative in all respects and not restrictive.

Claims (9)

A novel 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, except when all of them are hydrogen. According to claim 1,
The halogen is a compound or a pharmaceutically acceptable salt thereof, characterized in that selected from F, Cl, Br or I. According to claim 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 compound groups.

A transglutaminase-2 activity inhibitor comprising the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof. A pharmaceutical for preventing or treating diseases caused by increased transglutaminase-2 activity, characterized in that it contains the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof. composition. 6. The method of claim 5,
The disease is a neurological disease or a pharmaceutical composition for the prevention or treatment of a disease caused by an increase in transglutaminase-2 activity, characterized in that the cancer. 7. The method of claim 6,
The nervous system disease is Alzheimer's disease, multi-infarct dementia, a mixed type of Alzheimer's disease and multi-infarct dementia, Parkinson's disease, hypothyroidism, alcoholic dementia Transglutaminase-2, characterized in that selected from the group consisting of Alzheimer's disease and Huntington's disease A pharmaceutical composition for preventing or treating diseases caused by increased activity. 7. The method of claim 6,
The cancer is colon cancer, small intestine cancer, rectal cancer, anal cancer, esophageal cancer, pancreatic cancer, stomach cancer, kidney cancer, uterine cancer, breast cancer, lung cancer, lymph gland cancer, thyroid cancer, prostate cancer, leukemia, skin cancer, colon cancer, brain tumor, bladder cancer, ovarian cancer and A pharmaceutical composition for preventing or treating diseases caused by increased transglutaminase-2 activity, characterized in that it is selected from the group consisting of gallbladder cancer. 9. The method of claim 8,
The kidney cancer is clear cell RCC, papillary RCC, chromophobe RCC, collecting tube RCC, and urothelial cancer, transitional A pharmaceutical composition for preventing or treating diseases caused by increased transglutaminase-2 activity, characterized in that it is selected from the group consisting of cell carcinoma, TCC).