WO2024196053A1 - Estrogen-related receptor gamma inhibitor, and composition for combination therapy with anticancer drug - Google Patents

Abstract

The present invention relates to an estrogen-related receptor gamma inhibitor, and a composition for combination therapy with an anticancer drug. More specifically, provided is a composition for enhancing anticancer effects of a targeted anticancer drug or cytotoxic anticancer drug, or a composition for combination therapy for cancer prevention or treatment, the compositions containing an ERR γ inhibitor as an active ingredient. The ERR γ inhibitor is co-administered with an AKT inhibitor, a VEGFR inhibitor, or a cytotoxic anticancer drug, and thus can enhance the efficacy of the anticancer drug and, simultaneously, minimize toxicity and side effects of the anticancer drug.

Description

Composition for combination therapy of estrogen-linked receptor gamma inhibitor and anticancer agent

The present invention relates to a composition for combination therapy of an estrogen-related receptor gamma (ERR γ) inhibitor and an anticancer agent, and more specifically, to a composition for enhancing an anticancer effect by co-administering an ERR γ inhibitor and a targeted anticancer agent or a cytotoxic anticancer agent.

When cells in our body do not differentiate normally due to various causes and continue to grow, it is called a tumor. Tumors include benign tumors and malignant tumors. Among them, malignant tumors are called cancer. Cancer cells have the characteristics of not dividing normally, growing uncontrolled, infiltrating (invading) into surrounding tissues, and spreading to distant tissues and growing (metastasis).

One in four people in our country die from cancer, and the incidence of cancer is increasing significantly every year. This phenomenon is common not only in our country, but also in most countries, including the United States and Japan, and among the many diseases that mankind has not been able to overcome, cancer is the disease that poses the greatest threat to us.

The treatment methods for cancer are largely divided into three types: surgery, chemotherapy, and radiotherapy. In addition, there are local treatment, hormone therapy, photodynamic therapy, laser therapy, etc., and recently, immunotherapy and gene therapy have been included. Among them, anticancer drugs in chemotherapy have different pharmacological actions depending on the type of cancer, and various side effects due to toxicity appear, which is pointed out as a problem in cancer treatment. In addition, there is a problem that cancer cells with drug resistance can be generated due to long-term chemotherapy. Therefore, it is necessary to develop drugs that can maximize the efficacy of anticancer drugs while minimizing side effects.

The purpose of the present invention is to provide a composition having an excellent anticancer therapeutic effect when administered in combination with a conventional anticancer agent, more specifically, a targeted anticancer agent or a cytotoxic anticancer agent.

To achieve the above purpose, the present invention provides a pharmaceutical composition for enhancing the anticancer effect of an anticancer agent, containing a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient:

<Chemical formula 1>

The present invention provides a pharmaceutical composition for combination administration for preventing or treating cancer, comprising a compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof; and an AKT inhibitor or a pharmaceutically acceptable salt thereof as active ingredients.

The present invention provides a pharmaceutical composition for combination administration for preventing or treating cancer, comprising as active ingredients a compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof; and a vascular endothelial growth factor receptor (VEGFR) inhibitor or a pharmaceutically acceptable salt thereof.

In addition, the present invention provides a pharmaceutical composition for combination administration for preventing or treating cancer, containing a compound represented by the chemical formula 1 or a pharmaceutically acceptable salt thereof; and doxorubicin as active ingredients.

The present invention relates to a novel use of an estrogen-related receptor gamma (ERR γ) inhibitor, wherein the ERR γ inhibitor can enhance the anticancer effect of an AKT inhibitor or VEGFR inhibitor targeted anticancer agent or a cytotoxic anticancer agent.

Accordingly, by co-administering the ERR γ inhibitor with an AKT inhibitor or VEGFR inhibitory target anticancer agent or a cytotoxic anticancer agent, the efficacy of the anticancer agent is enhanced while reducing the dosage of the anticancer agent, thereby minimizing the toxicity and side effects of the anticancer agent, thereby improving problems due to side effects, and thus more effectively preventing, treating or improving cancer diseases.

Figure 1 shows the effect of the combination of MK2206 and DN200434 on the viability of colon cancer cells. Colon cancer cells were exposed to MK2206 (10 μM), DN200434 (25 μM), and the combination of the two drugs for 24 hours, and the viability of each cell was confirmed using the CCK-8 assay.

Figure 2 shows the in vivo confirmation of the effect of the combination of MK2206 and DN200434 on colon cancer growth. The mouse colon cancer tumor model was orally administered with 100 mg/kg MK2206 and 20 mg/kg DN200434 alone or in combination for 20 days, and the tumor volume and body weight were measured on specific dates.

Figure 3 shows the effect of the combination of doxorubicin and DN200434 on the viability of ovarian cancer cells. Ovarian cancer cells were exposed to doxorubicin (1 μM), DN200434 (20 μM), and the combination of the two drugs for 24 hours, and the viability of each cell was confirmed using the CCK-8 assay.

Figure 4 shows the effect of the combination of Lenvatinib and DN200434 on the survival rate of thyroid cancer cells. The survival rates of HTh-7 and TPC-1 cells were confirmed using the CCK-8 assay after 24 hours of exposure to Lenvatinib (10 μM), DN200434 (25 μM), and the combination of the two drugs.

Figure 5 shows the effect of the combination of Sorafenib and DN200434, a multi-kinase inhibitor, on the viability of thyroid cancer cells according to a comparative example of the present invention. After exposure to Sorafenib (1 μM), DN200434 (25 μM), and the combination of the two drugs for 24 hours, the viability of HTh-7 cells was confirmed using the CCK-8 assay.

Hereinafter, the present invention will be described in detail.

The present inventors have completed the present invention by confirming that when an ERR γ inhibitor is administered in combination with an AKT inhibition target anticancer agent, a VEGFR inhibition target anticancer agent, or doxorubicin, a cytotoxic anticancer agent, the compound exhibits significantly superior anticancer activity in cancer cells than when each compound is administered alone.

The present invention provides a pharmaceutical composition for enhancing the anticancer effect of an anticancer agent, containing a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient:

<Chemical formula 1>

The compound is a biocompatible and orally administrable estrogen-related receptor gamma (ERR γ) inhibitor.

The above compound can be used in the form of a pharmaceutically acceptable salt within the range having the same efficacy.

As used herein, “pharmaceutically acceptable” means a salt that is non-toxic to cells or humans exposed to the composition and has a safety and efficacy profile suitable for administration to humans.

The above salt can be used in the form of either a pharmaceutically acceptable basic salt or an acid salt. The basic salt can be used in the form of either an organic basic salt or an inorganic basic salt, and can be selected from the group consisting of a sodium salt, a potassium salt, a calcium salt, a lithium salt, a magnesium salt, a cesium salt, an aluminum salt, an ammonium salt, a triethylaminium salt, and a pyridinium salt. The acid salt is useful as an acid addition salt formed by a free acid. Inorganic acids and organic acids can be used as the free acid, and inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, sulfurous acid, phosphoric acid, diphosphoric acid, nitric acid, etc., and organic acids include citric acid, acetic acid, maleic acid, malic acid, fumaric acid, gluconic acid, methanesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, oxalic acid, malonic acid, glutaric acid, acetic acid, glycolic acid, succinic acid, tartaric acid, 4-toluenesulfonic acid, galacturonic acid, embonic acid, glutamic acid, citric acid, aspartic acid, stearic acid, etc., but are not limited thereto, and all salts formed using various inorganic acids and organic acids commonly used in the art can be included.

In addition, the compound may include not only the salts mentioned above, but also all salts, hydrates, solvates, derivatives, etc. that can be prepared by a conventional method. The addition salt may be prepared by a conventional method, and may be prepared by dissolving in a water-miscible organic solvent such as acetone, methanol, ethanol, or acetonitrile, adding an excess amount of organic base, or adding an aqueous base solution of an inorganic base, and then precipitating or crystallizing. Alternatively, the addition salt may be obtained by evaporating the solvent or the excess amount of base from the mixture and then drying, or the precipitated salt may be prepared by suction filtration.

The above anticancer agent may be a targeted anticancer agent that inhibits AKT, a targeted anticancer agent that inhibits VEGFR, or a cytotoxic anticancer agent.

The above AKT is a type of serine/threonine kinase that is activated in various types of cancer and promotes tumor progression and drug resistance.

The above AKT inhibitor may be at least one selected from the group consisting of MK2206, Ipatasertib and Capivasertib, preferably, but not limited to, MK2206.

The above MK2206 is an allosteric inhibitor represented by the following chemical formula 2, and is a pan-AKT inhibitor that does not specifically inhibit AKT1, AKT2, or AKT3:

<Chemical formula 2>

According to one experimental example of the present invention, it was confirmed that the anticancer effect was significantly improved when DN200434, an ERR γ inhibitor, and MK2206, an AKT inhibitor, were co-administered.

The above-mentioned vascular endothelial growth factor receptor (VEGFR) inhibitory target anticancer agent can be utilized in various types of cancer by inhibiting tumor cell angiogenesis and thus blocking tumor growth and metastasis.

Specifically, the VEGFR inhibitor may be at least one selected from the group consisting of Lenvatinib, Axitinib and Motesanib, preferably Lenvatinib, but is not limited thereto.

According to one experimental example of the present invention, it was confirmed that when lenvatinib was co-administered with DN200434, an ERR γ inhibitor, the anticancer effect in thyroid cancer cells was significantly enhanced, whereas according to one comparative example of the present invention, when sorafenib, another multi-kinase inhibitor, and DN200434, an ERR γ inhibitor, were co-administered, no significant enhancement of the anticancer effect was confirmed.

The above cytotoxic anticancer agent may be at least one selected from the group consisting of doxorubicin, cisplatin, and 5-FU (Fluorouracil), and is preferably doxorubicin, but is not limited thereto.

According to one experimental example of the present invention, it was confirmed that the anticancer effect was significantly improved when DN200434, an ERR γ inhibitor, and doxorubicin, a cytotoxic anticancer agent, were co-administered.

The cancer may be colon cancer, ovarian cancer, thyroid cancer, breast cancer, prostate cancer, lung cancer, osteosarcoma, bone cancer, pancreatic cancer, skin cancer, oral cancer, oropharyngeal cancer, uterine cancer, rectal cancer, stomach cancer, endometrial cancer, cervical cancer, vaginal cancer, small intestine cancer, brain tumor, brain cancer, melanoma, lymphoma, chronic or acute leukemia, bladder cancer, kidney cancer or liver cancer, and preferably, colon cancer or ovarian cancer, but is not limited thereto.

The pharmaceutical composition according to the present invention can be prepared according to a conventional method in the pharmaceutical field. The pharmaceutical composition can be combined with an appropriate pharmaceutically acceptable carrier according to the formulation, and, if necessary, can be prepared by further including an excipient, a diluent, a dispersant, an emulsifier, a buffer, a stabilizer, a binder, a disintegrant, a solvent, etc. The appropriate carrier, etc., does not inhibit the activity and properties of the compound according to the present invention or a pharmaceutically acceptable salt thereof, and can be selected differently according to the dosage form and formulation.

The above pharmaceutical composition can be applied in any dosage form, and more specifically, it can be formulated and used as an oral dosage form, an external preparation, a suppository, and a parenteral dosage form of a sterile injectable solution according to a conventional method.

Among the oral dosage forms, the solid dosage forms are in the form of tablets, pills, powders, granules, capsules, etc., and can be prepared by mixing at least one excipient, such as starch, calcium carbonate, sucrose, lactose, sorbitol, mannitol, cellulose, gelatin, etc., and may include lubricants such as magnesium stearate and talc in addition to simple excipients. In addition, in the case of a capsule dosage form, a liquid carrier such as fatty oil may be further included in addition to the above-mentioned substances. Among the oral dosage forms, the liquid dosage forms include suspensions, oral solutions, emulsions, syrups, etc., and in addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included.

The above parenteral formulations may include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, and 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. Suppository bases may include witepsol, macrogol, Tween 61, cacao butter, laurin butter, glycerogelatin, and the like. Without being limited thereto, any suitable formulation known in the art may be used.

In the pharmaceutical composition according to the present invention, the pharmaceutical composition can be administered in a pharmaceutically effective amount.

As used herein, “pharmaceutically effective amount” means an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment and without causing adverse effects.

The effective dosage level of the pharmaceutical composition may vary depending on the intended use, the patient's age, sex, weight and health condition, the type and severity of the disease, the activity of the drug, the sensitivity to the drug, the method of administration, the time of administration, the route of administration and the excretion rate, the duration of treatment, the drugs being combined or used simultaneously, and other factors well known in the medical field. For example, although not constant, it may generally be administered at 0.001 to 1000 mg/kg, preferably 0.01 to 100 mg/kg, once or several times a day. The above dosage does not limit the scope of the present invention in any way.

The pharmaceutical composition according to the present invention can be administered to any animal capable of developing cancer, and the animal can include, for example, humans and primates, as well as livestock such as cows, pigs, horses, and dogs.

The above pharmaceutical composition can be administered by an appropriate route of administration according to the form of the preparation, and can be administered by various routes, either oral or parenteral, as long as it can reach the target tissue. The method of administration is not particularly limited, and can be administered by conventional methods such as oral, rectal, intravenous, intramuscular, skin application, respiratory inhalation, intrauterine epidural or intracerebroventricular injection, etc.

The above pharmaceutical composition can be used to prevent or treat cancer by enhancing anticancer effects, and can be used in combination with surgery or other drug treatments.

The present invention provides a pharmaceutical composition for combination administration for preventing or treating cancer, comprising a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof; and an AKT inhibitor or a pharmaceutically acceptable salt thereof as active ingredients:

<Chemical formula 1>

The above AKT inhibitor may be at least one selected from the group consisting of MK2206, Ipatasertib and Capivasertib, preferably, but not limited to, MK2206.

The composition may contain the compound or a salt thereof; and the AKT inhibitor and a salt thereof in a molar ratio of 1: (0.1 to 1), preferably, but not limited to, in a molar ratio of 1:0.5.

The cancer may be colon cancer, ovarian cancer, thyroid cancer, breast cancer, prostate cancer, lung cancer, osteosarcoma, bone cancer, pancreatic cancer, skin cancer, oral cancer, oropharyngeal cancer, uterine cancer, rectal cancer, stomach cancer, endometrial cancer, cervical cancer, vaginal cancer, small intestine cancer, brain tumor, brain cancer, melanoma, lymphoma, chronic or acute leukemia, bladder cancer, kidney cancer or liver cancer, and preferably, colon cancer or ovarian cancer, but is not limited thereto.

Corresponding features can be substituted for those described above.

The present invention provides a pharmaceutical composition for combination administration for preventing or treating cancer, comprising a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof; and a vascular endothelial growth factor receptor (VEGFR) inhibitor or a pharmaceutically acceptable salt thereof as active ingredients:

<Chemical formula 1>

The above VEGFR inhibitor may be at least one selected from the group consisting of Lenvatinib, Axitinib and Motesanib, preferably Lenvatinib, but is not limited thereto.

The composition may contain the compound or a salt thereof and the VEGFR inhibitor or a salt thereof in a molar ratio of 1: (0.1 to 1), preferably in a molar ratio of 1: (0.3 to 0.5), but is not limited thereto.

The cancer may be thyroid cancer, colon cancer, ovarian cancer, breast cancer, prostate cancer, lung cancer, osteosarcoma, bone cancer, pancreatic cancer, skin cancer, oral cancer, oropharyngeal cancer, uterine cancer, rectal cancer, stomach cancer, endometrial cancer, cervical cancer, vaginal cancer, small intestine cancer, brain tumor, brain cancer, melanoma, lymphoma, chronic or acute leukemia, bladder cancer, kidney cancer or liver cancer, and preferably, thyroid cancer, but is not limited thereto.

Corresponding features can be substituted for those described above.

In addition, the present invention provides a pharmaceutical composition for combination administration for preventing or treating cancer, comprising a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof; and doxorubicin as active ingredients:

<Chemical formula 1>

The composition may contain the compound or a salt thereof; and the doxorubicin in a molar ratio of 1: (0.01 to 0.5), preferably, but not limited to, 1:0.05.

The cancer may be thyroid cancer, colon cancer, ovarian cancer, breast cancer, prostate cancer, lung cancer, osteosarcoma, bone cancer, pancreatic cancer, skin cancer, oral cancer, oropharyngeal cancer, uterine cancer, rectal cancer, stomach cancer, endometrial cancer, cervical cancer, vaginal cancer, small intestine cancer, brain tumor, brain cancer, melanoma, lymphoma, chronic or acute leukemia, bladder cancer, kidney cancer or liver cancer, and preferably, thyroid cancer, but is not limited thereto.

Corresponding features can be substituted for those described above.

Hereinafter, in order to help understand the present invention, examples will be given and described in detail. However, the following examples are only intended to illustrate the content of the present invention, and the scope of the present invention is not limited to the following examples. The examples of the present invention are provided to more completely explain the present invention to a person having average knowledge in the art.

<Experimental Method>

1. Preparation of cell lines

Human anaplastic thyroid cancer cells, HTh-7 and TPC-1, were cultured at 37°C in 5% CO2 using Dulbecco's modified Eagle's medium (DMEM high glucose; HyClone, Logan, UT, USA) supplemented with 10% fetal bovine serum ( _FBS ; Gibco, Grand Island, NY, USA) and 1% penicillin-streptomycin (Gibco, Carlsbad, CA, USA).

Human colon cancer cells HCT-116, SW-480, HT-29, and HCT-15 and human ovarian cancer cells OVCAR-3 were cultured at 37°C in 5% CO 2 using Dulbecco's modified Eagle's medium (DMEM high glucose; HyClone, Logan, UT, USA) supplemented with 10% fetal bovine serum ( _FBS ; Gibco, Grand Island, NY, USA) and 1% penicillin-streptomycin (Gibco, Carlsbad, CA, USA).

2. Cell viability analysis

After drug treatment, cell viability was determined using a Cell Counting Kit-8 (Dojindo molecular technologies, MD, USA). Each cell was seeded in a 96-well plate with a transparent bottom, and after 24 hours, each drug was treated alone or in combination, and 10 μl/well CCK-8 assay agent was treated at the specified time. After storage for 90 minutes under conditions of 37°C and 5% _CO2 , the absorbance was measured at 450 nm using a plater reader (BioTek instruments, Winooski, USA).

3. in vivo Colon cancer efficacy assessment

Six-week-old female BALB/c nude mice free of specific pathogens were purchased from SLC, Inc. (Shizuoka, Japan). All animals were cared for and used in accordance with the guidelines for the care and use of laboratory animals of the Daegu-Gyeongbuk Medical Industry Promotion Foundation Laboratory Animal Center. Animal experiments were conducted after approval by the Institutional Review Board for Animal Experiments of the Daegu-Gyeongbuk Medical Industry Promotion Foundation (Approval Number: DGMIF-17120802-00).

To establish a colorectal cancer xenograft model, 5 million HCT-116 cells were administered subcutaneously to mice. When the tumor size reached less than 150 mm ³ , the tumor-bearing mice were divided into four groups (n = 7) as follows:

Group 1, vehicle;

Group 2, 20 mg/kg DN200434 tunicamycin (oral) administered daily for 20 days;

Group 3, 100 mg/kg MK2206 (oral tour) administered daily for 20 days;

Group 4, 20 mg/kg DN200434 + 100 mg/kg MK2206 (both drugs administered orally) daily for 20 days.

No weight loss or abnormal behavior was observed in any mice during in vivo treatment. Tumor size was measured with a caliper at the indicated times, and tumor volume (mm ³ ) was calculated using the following equation:

<Formula 1>

Tumor volume (mm ³ ) = d2 × D/2

(Here, d and D represent the shortest and longest diameters in mm, respectively).

<Experimental Example 1> Confirmation of synergistic antiproliferative effect of combined use with MK2206 (AKT inhibitor) and DN200434 in colon cancer cells

The effect of the combination of MK2206 and DN200434 on cell proliferation of colon cancer cells using the CCK-8 assay was investigated. As shown in Fig. 1, treatment with MK2206 or DN200434 alone slightly decreased cell viability in colon cancer cells, but interestingly, the combination of MK2206 and DN200434 synergistically inhibited cell proliferation in colon cancer cells.

<Experimental Example 2> Combined use of DN200434 and MK2206 in a colon cancer model in vivo Confirmation of anticancer activity

Referring to Fig. 2, it was observed that tumor growth was very rapid in vehicle-treated mice. The 100 mg/kg MK2206 group or the 20 mg/kg DN200434 group showed weak anticancer efficacy, but no statistical significance was detected in either group. Interestingly, in the case of the 100 mg/kg MK2206 + 20 mg/kg DN200434 concurrent administration group, tumor growth was significantly delayed compared to the single administration group, and significance was also detected.

<Experimental Example 3> Confirmation of synergistic antiproliferative effect of combined use with Doxorubicin and DN200434 in ovarian cancer cells

The effect of the combination of doxorubicin and DN200434 on cell proliferation of ovarian OVCAR-3 cancer cells using the CCK-8 assay was investigated. As shown in Fig. 3, treatment with doxorubicin or DN200434 alone slightly decreased the cell viability of ovarian cancer cells, and interestingly, the combination of doxorubicin and DN200434 synergistically inhibited cell proliferation in ovarian cancer cells.

<Experimental Example 4> Confirmation of synergistic antiproliferative effect of combined use of Lenvatinib and DN200434 in thyroid cancer cells

The effect of the combination of DN200434 and Lenvatinib on cell proliferation of thyroid cancer cells (HTH-7 and TPC-1) using the CCK-8 assay was investigated.

As a result, as shown in Fig. 4, monotherapy with Lenvatinib or DN200434 decreased the cell viability of HTh-7 to 7.6±4.6% and 18.8±0.9%, respectively, and interestingly, the combination of Lenvatinib and DN200434 synergistically inhibited cell proliferation in HTh-7, showing a cell viability of 59.8±2.8%.

Similarly, treatment with Lenvatinib or DN200434 alone reduced the cell viability of TPC-1 to 23.2±2.5% and 2.8±1.4%, respectively, while combined treatment with Lenvatinib and DN200434 significantly reduced the cell viability to 59.8±2.8%.

<Comparative Example 1> Confirmation of antiproliferative effect of combined use with Sorafenib and DN200434 in thyroid cancer cells

The effect of DN200434 and sorafenib (as a multikinase inhibitor) combination on cell proliferation of HTh-7 cells was investigated using the CCK-8 assay. Referring to Fig. 5, it was confirmed that sorafenib monotherapy induced a slight decrease in cell viability in HTh-7 cells, but the combination of DN200434 and sorafenib alone could not induce a decrease in cell viability in HTh-7 cells.

While the specific parts of the present invention have been described in detail above, it is obvious to those skilled in the art that such specific description is merely a preferred embodiment and that the scope of the present invention is not limited thereby. In other words, the actual scope of the present invention is defined by the appended claims and their equivalents.

Claims (17)

A pharmaceutical composition for enhancing the anticancer effect of an anticancer agent, comprising a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient: <Chemical formula 1>

In paragraph 1, The above anticancer agent is, A pharmaceutical composition characterized by being a targeted anticancer agent selected from an AKT inhibitor or a vascular endothelial growth factor receptor (VEGFR) inhibitor; or a cytotoxic anticancer agent. In the second paragraph, The above AKT inhibitors are, A pharmaceutical composition characterized by comprising at least one selected from the group consisting of MK2206, Ipatasertib, and Capivasertib. In the second paragraph, The above VEGFR inhibitors are, A pharmaceutical composition characterized by comprising at least one selected from the group consisting of lenvatinib, axitinib, and motesanib. In the second paragraph, The above cytotoxic anticancer agent is, A pharmaceutical composition characterized by comprising at least one selected from the group consisting of doxorubicin, cisplatin, and 5-FU (Fluorouracil). In paragraph 1, The above cancer, A pharmaceutical composition characterized in that the cancer is colon cancer, ovarian cancer, thyroid cancer, breast cancer, prostate cancer, lung cancer, osteosarcoma, bone cancer, pancreatic cancer, skin cancer, oral cancer, oropharyngeal cancer, uterine cancer, rectal cancer, stomach cancer, endometrial cancer, cervical cancer, vaginal cancer, small intestine cancer, brain tumor, brain cancer, melanoma, lymphoma, chronic or acute leukemia, bladder cancer, kidney cancer or liver cancer. A pharmaceutical composition for combination administration for preventing or treating cancer, comprising a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof; and an AKT inhibitor or a pharmaceutically acceptable salt thereof as active ingredients: <Chemical formula 1>

In paragraph 7, The above AKT inhibitors are, A pharmaceutical composition characterized by comprising at least one selected from the group consisting of MK2206, Ipatasertib, and Capivasertib. In paragraph 7, The above composition, A pharmaceutical composition characterized in that the compound or a salt thereof and the AKT inhibitor or a salt thereof are contained in a molar ratio of 1: (0.1 to 1). In paragraph 7, The above cancer, A pharmaceutical composition characterized in that the cancer is colon cancer, ovarian cancer, thyroid cancer, breast cancer, prostate cancer, lung cancer, osteosarcoma, bone cancer, pancreatic cancer, skin cancer, oral cancer, oropharyngeal cancer, uterine cancer, rectal cancer, stomach cancer, endometrial cancer, cervical cancer, vaginal cancer, small intestine cancer, brain tumor, brain cancer, melanoma, lymphoma, chronic or acute leukemia, bladder cancer, kidney cancer or liver cancer. A pharmaceutical composition for combination administration for preventing or treating cancer, comprising a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof; and a vascular endothelial growth factor receptor (VEGFR) inhibitor or a pharmaceutically acceptable salt thereof as active ingredients: <Chemical formula 1>

In Article 11, The above VEGFR inhibitors are, A pharmaceutical composition characterized by comprising at least one selected from the group consisting of lenvatinib, axitinib, and motesanib. In Article 11, The above composition, A pharmaceutical composition characterized in that the compound or a salt thereof and the VEGFR inhibitor or a salt thereof are contained in a molar ratio of 1: (0.1 to 1). In Article 11, The above cancer, A pharmaceutical composition characterized in that the cancer is colon cancer, ovarian cancer, thyroid cancer, breast cancer, prostate cancer, lung cancer, osteosarcoma, bone cancer, pancreatic cancer, skin cancer, oral cancer, oropharyngeal cancer, uterine cancer, rectal cancer, stomach cancer, endometrial cancer, cervical cancer, vaginal cancer, small intestine cancer, brain tumor, brain cancer, melanoma, lymphoma, chronic or acute leukemia, bladder cancer, kidney cancer or liver cancer. A pharmaceutical composition for combination administration for the prevention or treatment of cancer, comprising a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof; and doxorubicin as an active ingredient: <Chemical formula 1>

In Article 15, The above composition, A pharmaceutical composition characterized in that the compound or a salt thereof; and the doxorubicin are contained in a molar ratio of 1: (0.01 to 0.5). In Article 15, The above cancer, A pharmaceutical composition characterized in that the cancer is colon cancer, ovarian cancer, thyroid cancer, breast cancer, prostate cancer, lung cancer, osteosarcoma, bone cancer, pancreatic cancer, skin cancer, oral cancer, oropharyngeal cancer, uterine cancer, rectal cancer, stomach cancer, endometrial cancer, cervical cancer, vaginal cancer, small intestine cancer, brain tumor, brain cancer, melanoma, lymphoma, chronic or acute leukemia, bladder cancer, kidney cancer or liver cancer.

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