Pharmaceutical composition for prevention or treatment of breast cancer

Abstract

The present invention relates to a use of a novel compound for the prevention, alleviation, or treatment of breast cancer, the novel compound of the present invention not only being capable of notably inhibiting the growth, proliferation, migration, carcinogenicity, and metastasis of breast cancer cells, but also being capable of simultaneously inhibiting ANO1 and EGFR in breast cancer cells, thereby being capable of exhibiting a stronger anticancer effect through the dual inhibition of the two proteins. In addition, the compound, when used in combination with an anticancer agent, may further enhance the efficacy of the anticancer agent, and may inhibit the resistance of the cancer. Thus, the compound itself may be used as a dual-target anticancer agent against ANO1 and EGFR, and may also be utilized as a combined preparation of an anticancer agent, and thus is expected to be utilized in various ways in the field of breast cancer prevention and treatment.

Description

Pharmaceutical composition for the prevention or treatment of breast cancer

[0001] The present invention relates to the use of novel compounds for preventing, improving, or treating breast cancer.

[0002] This invention claims priority from Korean Patent Application No. 10-2023-0162398, filed November 21, 2023, and the invention claims priority from Korean Patent Application No. 10-2024-0166743, filed November 20, 2024, the entire contents of which are incorporated herein by reference.

[0003]

[0004] Breast cancer refers to cancer that arises in the ducts and lobules of the breast. Various factors, including female hormone use, family history, past medical history, childbearing history, and dietary habits, have been suggested as possible causes of breast cancer, but none have been clearly identified. The incidence of breast cancer in modern women is rapidly increasing, and the incidence is also increasing in women in their 20s and 30s, due to factors such as low birth rates, short breastfeeding periods, early menarche, and late menopause.

[0005] Clinically, breast cancer is classified into three subgroups based on the expression of key genes: 1) estrogen receptor-positive (ER-positive) that expresses estrogen receptor (ER), 2) HER2-positive (HER2-positive) that expresses HER2, and 3) triple-negative breast cancer that does not express any of the three genes: estrogen receptor, progesterone receptor (PR), and HER2.

[0006] EGFR (epidermal growth factor receptor) is a receptor for EGF (epidermal growth factor), a peptide that promotes the growth of breast cancer cells. It exists throughout the cell membrane, activating EGF, transforming growth factor α, and tyrosine kinase to promote cell growth and DNA synthesis. EGFR is observed not only in breast cancer but also in lung cancer, stomach cancer, and liver cancer, and in particular, it is known to play an important role in carcinogenesis and tumor progression in breast cancer. In relation to the prognosis of breast cancer, EGFR expression is closely related to histologic grading and lymphatic invasion, and it is known that cases with EGFR positivity have a higher recurrence rate and mortality rate than cases with EGFR negativity.

[0007] Meanwhile, calcium-activated chloride channels (CaCC) are widely expressed in various cells and tissues and play a role in regulating physiological functions such as epithelial fluid secretion, smooth muscle contraction, sensory nerve signaling, and cell growth. After ANO1 / TMEM16A was discovered to be CaCC in 2008, various studies have revealed that ANO1 is highly expressed in various types of tumor cells such as bronchial, intestinal, glandular epithelial, smooth muscle, intestinal pacemaker cells, sensory nerves, and head and neck cancer, breast cancer, prostate cancer, and renal cancer, and has various physiological functions.

[0008] Anoctamin 1 (ANO1) is located on chromosome band 11q13 and is overexpressed in various cancer cells, including head and neck cancer, breast cancer, and prostate cancer. Recent studies have revealed that ANO1 is involved in cell growth, migration, tumorigenesis, and cancer development. For example, when ANO1 expression was suppressed in prostate cancer cells (PC3), cell growth, metastasis, invasion, and tumor development were inhibited in a mouse model, and T16Ainh-A01, an ANO1 inhibitor, inhibited the growth of stromal cells of Cajal (ICC) and pancreatic cancer cells (CFPAC1), which highly express ANO1. In addition, it was reported that when ANO1 expression was suppressed in breast cancer cells, breast cancer cell growth was inhibited, cancer cell death was induced, and tumor growth was inhibited in a xenograft model. Furthermore, inhibition of ANO1 has been shown to exert anticancer effects through inhibition of epidermal growth factor receptor (EGFR) and calmodulin-dependent protein kinase 2 (CAMK2) signaling in head and neck cancer (HNSCC), esophageal squamous cell carcinoma (ESCC), and breast cancer cells. Therefore, recent research results suggest that pharmacological inhibition of the ANO1 ion channel has potential as a treatment for head and neck cancer, esophageal cancer, gastrointestinal cancer, breast cancer, and prostate cancer that overexpress ANO1.

[0009] Thus, both ANO1 and EGFR proteins have potential as therapeutic targets for breast cancer. However, no agent capable of exhibiting superior anticancer effects through dual inhibition of ANO1 and EGFR has yet been discovered.

[0010]

[0011] The present inventors have completed the present invention by confirming that the novel compound of the present invention can exhibit excellent anticancer effects by inhibiting the growth, proliferation, migration, carcinogenesis, and metastasis of breast cancer cells and simultaneously inhibiting ANO1, a calcium-dependent chloride channel, and EGFR, an epidermal growth factor receptor, and also exhibiting a high synergistic effect when administered in combination with an anticancer agent.

[0012] Accordingly, the purpose of the present invention is to provide a pharmaceutical composition for preventing or treating breast cancer, which comprises a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0013] [Chemical Formula 1]

[0014]

[0015] Another object of the present invention is to provide (i) a compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof; and

[0016] (ii) It provides a pharmaceutical composition for preventing or treating breast cancer, comprising as an active ingredient at least one anticancer agent selected from the group consisting of chemotherapeutic anticancer agents and targeted anticancer agents.

[0017] Another object of the present invention is to provide a pharmaceutical composition for enhancing the anticancer effect of an anticancer agent for breast cancer, comprising a compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0018]

[0019] However, the technical problems to be solved by the present invention are not limited to the problems mentioned above, and other problems not mentioned can be clearly understood by a person having ordinary skill in the technical field to which the present invention belongs from the description below.

[0020]

[0021] To achieve the above purpose, the present invention provides a pharmaceutical composition for preventing or treating breast cancer, comprising a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0022] [Chemical Formula 1]

[0023]

[0024] In one embodiment of the present invention, the breast cancer may be at least one selected from the group consisting of breast intraepithelial carcinoma, inflammatory breast cancer, triple-negative breast cancer, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ (non-invasive), lobular carcinoma in situ (non-invasive), Paget's disease of the breast, invasive breast cancer, and metastatic breast cancer, but is not limited thereto.

[0025] In another embodiment of the present invention, the compound or a pharmaceutically acceptable salt thereof can simultaneously inhibit EGFR and ANO1, but is not limited thereto.

[0026] In another embodiment of the present invention, the compound or a pharmaceutically acceptable salt thereof may satisfy one or more properties selected from the group consisting of, but not limited to:

[0027] (a) inhibiting the proliferation or growth of cancer cells;

[0028] (b) inhibiting the migration of cancer cells;

[0029] (c) inhibiting the tumorigenicity of cancer cells;

[0030] (d) inhibiting cancer metastasis; and

[0031] (e) Inhibits cancer resistance to anticancer drugs.

[0032] In another embodiment of the present invention, the anticancer agent may be, but is not limited to, a chemotherapy agent or a targeted anticancer agent.

[0033] In another embodiment of the present invention, the chemotherapeutic agent may be at least one selected from the group consisting of paclitaxel, docetaxel, dactinomycin, doxorubicin, daunorubicin, mitomycin, and bleomycin, but is not limited thereto.

[0034] In another embodiment of the present invention, the targeted anticancer agent may be at least one selected from the group consisting of a targeted anticancer agent for EGFR, a targeted anticancer agent for TROP-2, and a targeted anticancer agent for PARP, but is not limited thereto.

[0035] In another embodiment of the present invention, the pharmaceutical composition may be administered in combination with, but is not limited to, a chemotherapeutic agent or a targeted anticancer agent.

[0036] In another embodiment of the present invention, the pharmaceutical composition may be administered simultaneously with, separately from, or sequentially with the anticancer agent, but is not limited thereto.

[0037] In addition, the present invention provides a pharmaceutical composition for preventing or treating breast cancer, comprising as active ingredients (i) a compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof; and (ii) at least one anticancer agent selected from the group consisting of a chemotherapeutic agent and a targeted anticancer agent.

[0038] In one embodiment of the present invention, the compound or a pharmaceutically acceptable salt thereof can suppress the resistance of cancer cells to the anticancer agent, but is not limited thereto.

[0039] In another embodiment of the present invention, the composition may be in the form of a mixture comprising the compound or a pharmaceutically acceptable salt thereof and the anticancer agent, but is not limited thereto.

[0040] In another embodiment of the present invention, the composition may be in a form in which the compound or a pharmaceutically acceptable salt thereof and the anticancer agent are each formulated and administered simultaneously, separately, or sequentially, but is not limited thereto.

[0041] In addition, the present invention provides a pharmaceutical composition for enhancing the anticancer effect of an anticancer agent for breast cancer, comprising a compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0042] In one embodiment of the present invention, the anticancer agent may be at least one selected from the group consisting of a chemotherapy agent and a targeted anticancer agent, but is not limited thereto.

[0043] In another embodiment of the present invention, the chemotherapeutic agent may be at least one selected from the group consisting of paclitaxel, docetaxel, dactinomycin, doxorubicin, daunorubicin, mitomycin, and bleomycin, but is not limited thereto.

[0044] In another embodiment of the present invention, the targeted anticancer agent may be at least one selected from the group consisting of a targeted anticancer agent for EGFR, a targeted anticancer agent for TROP-2, and a targeted anticancer agent for PARP, but is not limited thereto.

[0045] In another embodiment of the present invention, the composition may be administered simultaneously with, separately from, or sequentially with the anticancer agent, but is not limited thereto.

[0046] In addition, the present invention provides a method for preventing, improving, or treating breast cancer, comprising administering to a subject in need thereof a pharmaceutically effective amount of a compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof; or a composition comprising the same; or a method for enhancing the anticancer effect of an anticancer agent for breast cancer.

[0047] In addition, the present invention provides a compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof; or a composition comprising the same for use in preventing, improving, or treating breast cancer; or for use in enhancing the anticancer effect of an anticancer agent for breast cancer.

[0048] In addition, the present invention provides a use for producing a preparation for preventing, improving, or treating breast cancer, comprising a compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof; or a composition comprising the same; or a preparation for enhancing the anticancer effect of an anticancer agent for breast cancer.

[0049] In addition, the present invention provides a method for preventing, improving, or treating breast cancer, comprising administering to a subject in need thereof a pharmaceutically effective amount of (i) a compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof, and (ii) at least one anticancer agent selected from the group consisting of chemotherapeutic agents and targeted anticancer agents; or a composition comprising the same.

[0050] In addition, the present invention provides a use for preventing, improving, or treating breast cancer, comprising (i) a compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof, and (ii) at least one anticancer agent selected from the group consisting of a chemotherapeutic agent and a targeted anticancer agent; or a composition comprising the same.

[0051] In addition, the present invention provides a use for producing a preparation for preventing, improving, or treating breast cancer, comprising (i) a compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof, and (ii) at least one anticancer agent selected from the group consisting of a chemotherapeutic agent and a targeted anticancer agent; or a composition comprising them.

[0052]

[0053] The novel compound of the present invention not only significantly inhibits the growth, proliferation, migration, carcinogenesis, and metastasis of breast cancer cells, but also simultaneously inhibits ANO1 and EGFR in breast cancer cells, thereby exhibiting a more potent anticancer effect through dual inhibition of the two proteins. Furthermore, when used in combination with anticancer drugs, the efficacy of the anticancer drugs can be further enhanced and cancer resistance can be suppressed. Therefore, the compound can be used on its own as a dual-target anticancer drug targeting ANO1 and EGFR, and can also be utilized as a combination agent of anticancer drugs, and is therefore expected to have diverse applications in the fields of breast cancer prevention and treatment.

[0054]

[0055] Figure 1 shows the results of a CCK assay performed after treating human breast cancer cell line MDA-MB-231 cells with the compound AON-MG23 of the present invention at various concentrations to confirm the proliferation inhibitory effect of the compound AON-MG23 of the present invention on human breast cancer cells.

[0056] Figures 2a to 2c show the results of confirming the cell cluster formation ability after treating six breast cancer cell lines (SUM149, BCX010, BT20, MDA-MB-231-LM3, CAL51, PyMT-N) with the compound AON-MG23 of the present invention at various concentrations to confirm the proliferation inhibitory effect of the compound AON-MG23 of the present invention on human breast cancer cells.

[0057] FIG. 3a and FIG. 3b show the results of an attachment-independent soft agar assay performed after treating four breast cancer cell lines (SUM149, BCX010, BT20, MDA-MB-231-LM3) with the compound AON-MG23 of the present invention at various concentrations to confirm the tumorigenicity inhibitory effect of the compound AON-MG23 of the present invention on human breast cancer cells.

[0058] Figure 4 shows the results of photographing and analyzing the degree of cell migration over time after treating MDA-MB-231 cells, a human breast cancer cell line, with various concentrations of the compound AON-MG23 of the present invention to confirm the cell migration inhibitory effect of the compound AON-MG23 of the present invention on human breast cancer cells.

[0059] Figure 5 is a schematic diagram of an experiment to confirm the cell migration inhibitory effect of the compound AON-MG23 of the present invention.

[0060] Figure 6 shows the results of confirming the cell migration inhibitory effect of AON-MG23, a compound of the present invention, on MDA-MB-231-LM3 cells, a human breast cancer cell line, after pretreatment with a single concentration (0.5 μM) to confirm the mobility.

[0061] Figure 7 shows the results of photographing and analyzing the extent of cell penetration into Matrigel after treating human breast cancer cell line MDA-MB-231 cells cultured on Matrigel with various concentrations of compound AON-MG23 of the present invention to confirm the breast cancer cell metastasis inhibitory effect of compound AON-MG23 of the present invention.

[0062] Figure 8 shows the results of treating MDA-MB-231-LM3 cells, a human breast cancer cell line, with the compound AON-MG23 of the present invention at various concentrations to confirm the cell metastasis inhibitory effect on human breast cancer cells.

[0063] Figure 9 shows the results of confirming the effect of the compound AON-MG23 of the present invention on the expression of ANO1 protein and EGFR protein in human breast cancer cells.

[0064] Figures 10a and 10b show the results of confirming the combined effect of the compound AON-MG23 of the present invention with paclitaxel in human breast cancer cells. Figure 10a shows the human breast cancer cell line SUM149, and Figure 10b shows the human breast cancer cell line HCC1806.

[0065]

[0066] The present inventors have completed the present invention by confirming that the novel compound of the present invention can exhibit excellent anticancer effects by inhibiting the growth, proliferation, metastasis, carcinogenesis, and migration of breast cancer cells, and simultaneously inhibiting ANO1, a calcium-dependent chloride channel, and EGFR, an epidermal growth factor receptor, and also exhibiting a high synergistic effect when administered in combination with an anticancer agent.

[0067]

[0068] Hereinafter, the present invention will be described in detail.

[0069]

[0070] The present invention provides a pharmaceutical composition for preventing or treating breast cancer, comprising a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0071] [Chemical Formula 1]

[0072]

[0073] The compound represented by the above chemical formula 1 may be referred to as "N-(2-((5-chloro-2-((4-(4-(dimethylamino)piperidin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-cyclopropylmethanesulfonamide [N-(2-((5-chloro-2-((4-(4-(dimethylamino)piperidin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-cyclopropylmethanesulfonamide]" or "AON-MG23", and "Ms" in the chemical formula 1 means methylsulfonyl, i.e., -SO2(CH3).

[0074] Unless otherwise stated below, the terms “compound of the present invention” or “compound represented by Chemical Formula 1” are used as a concept including the compound represented by Chemical Formula 1 itself, its salt, and its isomers.

[0075] In the present invention, the term “pharmaceutically acceptable salt” includes all salts derived from pharmaceutically acceptable inorganic acids, organic acids, or bases.

[0076] As used herein, the term "pharmaceutically acceptable" means a compound or composition that is suitable for use in contact with the tissues of a subject (e.g., a human) without excessive toxicity, irritation, allergic response, or other problems or complications, and with a reasonable benefit / risk ratio, and is within the scope of sound medical judgment.

[0077] Examples of suitable acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, hydroiodic acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, (+)-L-tartaric acid, diL-tartaric acid, acetic acid, trichloroacetic acid or trifluoroacetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, 4-acetamidobenzoic acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphorsulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-Hydroxyethanesulfonic acid, galactaric acid, gentisic acid, glucoheptanoic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, a-oxo-glutaric acid, hippuric acid, (+)-L-lactic acid, (+-)-DL-lactic acid, lactobionic acid, (-)-L-malic acid, (+-)-DL-mandelic acid, citric acid, methanesulfonic acid, formic acid, benzoic acid, malonic acid, gluconic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, benzenesulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, di-oxalic acid, palmitic acid, pamoic acid, L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, Examples thereof include stearic acid, tannic acid, thiocyanic acid, camsylic acid, and undecylic acid. Acid addition salts can be prepared by conventional methods, for example, by dissolving the compound in an excess of an aqueous acid solution and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone, or acetonitrile. Alternatively, equimolar amounts of the compound and an acid or alcohol in water can be heated, and the mixture is then evaporated to dryness, or the precipitated salt can be filtered with suction.

[0078] The scope of the compounds of the present invention may include not only pharmaceutically acceptable salts, but also all isomers, hydrates and solvates that can be prepared by conventional methods.

[0079] In the present invention, the term "isomer" refers to a compound that has the same molecular formula but different connection methods or spatial arrangements of constituent atoms within the molecule. Isomers include, for example, structural isomers and stereoisomers. The stereoisomers may be diastereomers or enantiomers. Enantiomers are isomers that do not overlap with their mirror images, like the relationship between left and right hands, and are also called optical isomers. Enantiomers are classified as R (Rectus: clockwise) and S (Sinister: counterclockwise) when four or more substituents are different at the chiral center carbon. Diastereoisomers refer to stereoisomers that are not mirror images, and can be divided into cis-trans isomers that occur due to different spatial arrangements of atoms.

[0080] The compound of the present invention is characterized by exhibiting excellent anticancer effects by simultaneously inhibiting the expression or activity of EGFR and ANO1. The preventive and / or therapeutic effects on breast cancer include not only the effect of inhibiting the growth of breast cancer cells, but also the effect of inhibiting the progression or worsening of breast cancer due to migration, invasion, metastasis, and tumorigenicity.

[0081] In the present invention, "EGFR (epidermal growth factor receptor)" is a transmembrane glycoprotein that is a member of the protein kinase superfamily and is a receptor for epidermal growth factor family proteins. EGFR is a major regulator of cell growth, and when the ligand epidermal growth factor (EGF) binds to EGFR, the receptor dimerizes and undergoes tyrosine autophosphorylation, thereby inducing cell proliferation. Overexpression (amplification) or hyperactivity of EGFR is frequently observed in various cancers such as anal cancer, breast cancer (especially triple-negative breast cancer), and glioblastoma, and somatic mutations related to EGFR cause persistent activation of EGFR, leading to uncontrolled cell division. In particular, EGFR gene rearrangement and EGFR gene amplification are observed in various cancers.

[0082] In the present invention, "Anoctamin 1 (ANO1)" is a calcium-activated chloride ion channel (Cl), also referred to as "transmembrane protein 16A (TMEM16A)." -ANO1 is expressed in various normal cells including epithelial cells, smooth muscle cells, vascular endothelial cells, and neurons, and performs various physiological roles by regulating body fluid secretion, muscle contraction, and pain sensation. However, ANO1 is also known to be involved in cell carcinogenesis and cancer development. In fact, overexpression of ANO1 has been reported to promote signaling pathways that stimulate proliferation and migration in cancer cells, and inhibition of ANO1 inhibits cancer cell migration and growth. High expression of ANO1 appears to be associated with high expression of EGFR and STAT3, and inhibition of ANO1 is also known to improve the response of head and neck squamous cell carcinoma to EGFR / HER2 targeted therapy. Therefore, ANO1 is attracting attention as a target for cancer treatment, but an ANO1 inhibitor that actually exhibits excellent anticancer effects has not yet been discovered. The compound of the present invention has been confirmed to effectively suppress the expression of ANO1 in breast cancer cells and to inhibit the migration, proliferation, and metastasis of breast cancer cells, and thus can be used for the prevention, treatment, and metastasis suppression of breast cancer. Furthermore, previous studies on the improvement in the efficacy of EGFR / HER2 targeted therapy through ANO1 inhibition suggest that the compound of the present invention can enhance the responsiveness of cancer cells to EGFR / HER2 targeted therapy and suppress the development of resistance through the ANO1 inhibitory effect.

[0083] In particular, the compound of the present invention simultaneously inhibits the expression of EGFR together with ANO1 in breast cancer cells, and thus, the simultaneous inhibition of ANO1 and EGFR can exhibit a more potent anticancer effect. The relationship between ANO1 and EGFR is well known. The upregulation of ANO1 is related to the EGFR signaling pathway and has been reported to have a significant effect on the remodeling of the phosphorylated proteome after epidermal growth factor (EGF) stimulation. Furthermore, in cancer cells, ANO1 can form a functional complex with EGFR to jointly regulate cell proliferation. Therefore, the simultaneous inhibition of EGFR and ANO1 using the compound of the present invention can more effectively inhibit the growth of breast cancer.

[0084] Meanwhile, ANO1 is known to be overexpressed in cancer cells and contribute to cancer cell migration and tumor metastasis, and signaling through EGFR is also known to create a tumor microenvironment that is conducive to tumor metastasis. Therefore, the compound according to the present invention can effectively inhibit breast cancer metastasis through simultaneous inhibition of ANO1 and EGFR. The term "metastasis" refers to a state in which a malignant tumor has spread to other tissues distant from the organ in which it developed. Therefore, the composition according to the present invention can prevent and treat the spread of breast cancer throughout the body by inhibiting breast cancer metastasis.

[0085] In the present invention, "tumor" is used with the same meaning as "cancer", and typically refers to a condition characterized by uncontrolled cell growth, migration, and proliferation. Cancer according to the present invention is breast cancer, including primary and recurrent cancer, and both benign and malignant tumors. In the present invention, the breast cancer means all tumors that occur in the breast, and clinically, breast cancer can be classified into three subgroups according to the expression of major genes: 1) estrogen receptor-positive (ER-positive) that expresses estrogen receptor (ER), 2) HER2-positive (HER2-positive) that expresses HER2, and 3) triple-negative breast cancer that does not express any of the three genes of estrogen receptor, progesterone receptor (PR), and HER2. Additionally, it can be classified into non-invasive cancer and invasive cancer depending on whether the basement membrane is invaded, and can be classified into ductal cancer and lobular cancer depending on the gland tissue in which it develops.

[0086] In the present invention, the breast cancer may be at least one selected from the group consisting of breast intraepithelial carcinoma, inflammatory breast cancer, triple-negative breast cancer, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ (non-invasive), lobular carcinoma in situ (non-invasive), Paget's disease of the breast, invasive breast cancer, and metastatic breast cancer, and according to one embodiment of the present invention, the breast cancer may be at least one selected from the group consisting of breast intraepithelial carcinoma (SUM149 cells, SUM159 cells, CAL51 cells), inflammatory breast cancer (BCX010 cells, FC-IBC02 cells), triple-negative breast cancer (BT20 cells, MDA-MB-231-LM3 cells, PyMT-N cells, HCC 1806 cells, HCC 1937 cells), and metastatic breast cancer (MDA-MB-436 cells), but is not limited thereto.

[0087] The above "Carcinoma in Situ of Breast" is a type of non-invasive breast cancer in which cancer cells are confined to the epithelial tissue and do not invade the basement membrane of the milk duct. It includes lobular carcinoma in situ and ductal carcinoma in situ.

[0088] The above "inflammatory breast cancer" is one of the most lethal forms of advanced breast cancer, in which cancer cells directly and extensively invade the breast skin, causing symptoms similar to breast inflammation, and is a type of invasive breast cancer.

[0089] The above "Triple-Negative Breast Cancer (TNBC)" is a breast cancer in which estrogen and progesterone receptors are missing (ER- / PR-) and the HER2 gene is not expressed (HER2-). It has the characteristics of being resistant to taxol, tamoxifen, and HER2 inhibitor (trastuzumab), and it is known that EGFR, a cancer cell growth factor, is overexpressed.

[0090] The above-mentioned "metastatic breast cancer" refers to Stage 4 breast cancer, in which cancer cells have spread to other organs in the body and are difficult to cure. It is known to have a five-year survival rate of only 22%. Treatment is determined by considering factors such as the presence of hormone receptors (HR) or human epidermal growth factor receptor 2 (HER-2), the duration of cancer recurrence, the rate of metastasis progression, and the site of metastasis.

[0091] The above "Invasive Breast Cancer" is a cancer that has invaded the basement membrane of a duct or lobules, and includes invasive ductal cancer, invasive lobular cancer, mucinous cancer, medullary cancer, tubular cancer, adenoid cystic carcinoma, secretory carcinoma, apocrine carcinoma, and metaplastic carcinoma.

[0092] Furthermore, the breast cancer according to the present invention may be a breast cancer that is expected to be improved or treated by simultaneously inhibiting ANO1 and EGFR. Preferably, the breast cancer according to the present invention may be associated with one or more mutations selected from the group consisting of EGFR (Epidermal growth factor receptor) and ANO1 (Anoctamin 1). That is, the cancer according to the present invention may be a breast cancer having a mutation in EGFR and / or ANO1. The mutation in EGFR and / or ANO1 includes amplification of the gene of EGFR and / or ANO1, overexpression of the protein, overactivity of the protein, and persistent activation of the protein. That is, the breast cancer according to the present invention may have higher expression or activity of EGFR and / or ANO1 compared to normal cells. Alternatively, the breast cancer according to the present invention may have a persistent state of activation of EGFR and / or ANO1. Since the compound according to the present invention can simultaneously inhibit the expression and activity of ANO1 and EGFR, it can exhibit particularly excellent anticancer effects against breast cancer accompanied by mutations in EGFR and / or ANO1.

[0093] In the present invention, the compound or a pharmaceutically acceptable salt thereof can simultaneously inhibit EGFR and ANO1, but is not limited thereto.

[0094] In the present invention, the compound or a pharmaceutically acceptable salt thereof may satisfy one or more characteristics selected from the group consisting of, but is not limited to:

[0095] (a) inhibiting the proliferation or growth of cancer cells;

[0096] (b) inhibiting the migration of cancer cells;

[0097] (c) inhibiting the tumorigenicity of cancer cells;

[0098] (d) inhibiting cancer metastasis; and

[0099] (e) Inhibits cancer resistance to anticancer drugs.

[0100] In the present invention, the anticancer agent in (e) may be a chemotherapy anticancer agent and / or a targeted anticancer agent, but is not limited thereto.

[0101] The present inventors confirmed through specific examples that breast cancer cells treated with the compound according to the present invention exhibit inhibition of growth, proliferation, migration, carcinogenicity, and metastasis (invasiveness).

[0102] In the present invention, "tumorigenicity" means the ability or tendency to create cancer, and according to one embodiment of the present invention, it was shown that carcinogenicity was suppressed in a concentration-dependent manner in breast cancer cells (SUM149, BCX010, BT20, MDA-MB-231-LM3) treated with the compound according to the present invention.

[0103] Furthermore, the inventors of the present invention confirmed that the compound of the present invention can simultaneously inhibit ANO1 and EGFR (i.e., dual inhibition). Therefore, the compound of the present invention can exhibit a more excellent anticancer effect than a single inhibitor of ANO1 or EGFR, and in particular, can suppress the development of resistance of cancer cells to anticancer drugs through ANO1 inhibition and enhance the anticancer effect of the anticancer drug. For example, the inventors of the present invention confirmed through experiments that when the compound of the present invention is co-administered with the taxane-based chemotherapeutic agent paclitaxcel, it exhibits a high synergistic effect despite breast cancer cells (SUM149, HCC1806) being resistant to paclitaxcel. In addition, the inventors of the present invention confirmed that the compound of the present invention inhibits the growth and carcinogenicity of breast cancer cells SUM149 resistant to paclitaxel (taxane-based chemotherapeutic agent), Olaparib (PARP inhibitor), and Sacituzumab govitecan (TROP-2 targeting antibody), paclitaxel-resistant BCX010 and BT20, and doxorubicin-resistant breast cancer cells CAL51.

[0104] Therefore, in the present invention, the pharmaceutical composition may be administered in combination with a chemotherapeutic agent or a targeted anticancer agent, and the pharmaceutical composition may be administered simultaneously with, separately from, or sequentially with the anticancer agent, but is not limited thereto.

[0105] In the present invention, the "chemical anticancer agent" is a general term for a drug that acts directly on DNA to block the replication, transcription, and translation processes of DNA, or interferes with the synthesis of nucleic acid precursors in metabolic pathways and inhibits cell division, thereby exhibiting anticancer activity, i.e., cytotoxicity to cancer cells. In the present invention, the chemical anticancer agent may include paclitaxel and docetaxel, which are "taxane-based chemotherapeutic agents" that inhibit cell division of cancer cells by interfering with the separation process of microtubules, which are cell organelles involved in division and self-replication during cell division, and may include dr. nomycin, doxorubicin, daunorubicin, mitomycin, and bleomycin, which are "antibiotic-based chemotherapeutic agents" extracted from the soil fungus Streptomyces species, which intervene between base pairs of DNA as cell cycle non-specific drugs to unwind the DNA helix and interfere with DNA and RNA synthesis. That is, in the present invention, the chemotherapeutic agent may be at least one selected from the group consisting of paclitaxel, docetaxel, dactinomycin, doxorubicin, daunorubicin, mitomycin, and bleomycin, but is not limited thereto.

[0106] In the present invention, "targeted anticancer agent" means an agent that exhibits an anticancer effect by targeting a protein or gene that is specifically changed in cancer cells or cancer tissues and interfering with molecular activities involved in the growth and development of cancer. The targeted anticancer agent may be at least one selected from the group consisting of a targeted anticancer agent for EGFR, a targeted anticancer agent for TROP-2, and a targeted anticancer agent for PARP. The targeted anticancer agent for EGFR (EGFR inhibitor) may be cetuximab, osimertinib, gefitinib, afatinib, erlotinib, or lazertinib; the targeted anticancer agent for PARP (PARP inhibitor) may be olaparib, niraparib, rucaparib, or talazoparib; and the targeted anticancer agent for TROP-2 may be sacituzumab govitecan, but is not limited thereto, and any substance that targets EGFR, PARP, or TROP-2 may be included without limitation.

[0107] In addition, the compound according to the present invention can enhance the anticancer effect of an anticancer agent by increasing the activity of an anticancer agent against breast cancer or increasing the responsiveness of cancer cells to the anticancer agent.

[0108] The enhanced responsiveness of cancer cells to the above anticancer agent means that the inhibition of cancer cell growth, proliferation, migration, carcinogenesis, and metastasis by the anticancer agent are further enhanced.

[0109] In the present invention, “enhancing anticancer effect” refers to all effects that can ultimately strengthen the function of an anticancer agent, and is a concept that includes not only enhancing the anticancer effect of an anticancer agent, such as suppressing the growth of cancer cells, suppressing cancer metastasis, and suppressing cancer recurrence, but also suppressing the formation of resistance or tolerance in cancer cells to the anticancer agent, thereby ultimately enhancing the anticancer effect.

[0110] Therefore, the compound according to the present invention can be used as a compound for combined administration with known anticancer agents for the purpose of enhancing the anticancer effect of the anticancer agent.

[0111] For example, the present invention provides a pharmaceutical composition for preventing or treating breast cancer, comprising as active ingredients (i) a compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof; and (ii) at least one anticancer agent selected from the group consisting of a chemotherapeutic agent and a targeted anticancer agent.

[0112] In the present invention, the compound or a pharmaceutically acceptable salt thereof may suppress the resistance of cancer cells to the anticancer agent, but is not limited thereto.

[0113] In the present invention, the composition may be in the form of a mixture containing the compound or a pharmaceutically acceptable salt thereof and an anticancer agent, and may be in the form for simultaneous administration of the compound or a pharmaceutically acceptable salt thereof and the anticancer agent.

[0114] In the present invention, the composition may be in a form in which the compound or a pharmaceutically acceptable salt thereof; and the anticancer agent are each formulated and administered simultaneously, separately, or sequentially. In this case, the composition may be a pharmaceutical composition for combined administration for simultaneous or sequential administration, comprising a first pharmaceutical composition containing a pharmaceutically effective amount of the compound or its salt as an active ingredient; and a second pharmaceutical composition containing a pharmaceutically effective amount of the anticancer agent as an active ingredient. In this case, in the case of sequential administration, the administration order is not limited, and the administration regimen may be appropriately adjusted depending on the patient's condition, etc. That is, when the pharmaceutical composition is a pharmaceutical composition for combined administration for sequential administration, the composition may be such that the compound or its salt ("first component") is administered first and then the anticancer agent ("second component") is administered, or the reverse order is also possible.

[0115]

[0116] In addition, since the compound of the present invention can enhance the anticancer effect of an anticancer agent by increasing the activity of an anticancer agent for breast cancer or increasing the responsiveness of cancer cells to the anticancer agent, the present invention can provide a pharmaceutical composition for enhancing the anticancer effect of an anticancer agent for breast cancer, which comprises the compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0117] In the present invention, the anticancer agent may be at least one selected from the group consisting of a chemotherapy agent and a targeted anticancer agent, but is not limited thereto.

[0118] In the present invention, the chemotherapeutic agent may be at least one selected from the group consisting of paclitaxel, docetaxel, dactinomycin, doxorubicin, daunorubicin, mitomycin, and bleomycin, but is not limited thereto. According to one embodiment of the present invention, the chemotherapeutic agent may be paclitaxel, but is not limited thereto.

[0119] In the present invention, the targeted anticancer agent may be at least one selected from the group consisting of a targeted anticancer agent for EGFR, a targeted anticancer agent for TROP-2, and a targeted anticancer agent for PARP, but is not limited thereto.

[0120] In the present invention, the pharmaceutical composition may be administered simultaneously with, separately from, or sequentially with an anticancer agent, and the administration order is not limited, and the administration regimen may be appropriately adjusted depending on the type of cancer, the type of anticancer agent, the condition of the patient, etc.

[0121] The content of the compound in the composition of the present invention can be appropriately adjusted depending on the symptoms of the disease, the degree of progression of the symptoms, the condition of the patient, etc., and may be, for example, 0.0001 to 99.9 wt% or 0.001 to 50 wt% based on the total weight of the composition, but is not limited thereto. The content ratio is a value based on the dry amount after removing the solvent.

[0122] The pharmaceutical composition according to the present invention may further comprise suitable carriers, excipients, and diluents commonly used in the manufacture of pharmaceutical compositions. The excipients may be, for example, one or more selected from the group consisting of diluents, binders, disintegrants, lubricants, adsorbents, moisturizers, film-coating materials, and controlled-release additives.

[0123] The pharmaceutical composition according to the present invention may be formulated and used in the form of external preparations such as powders, granules, sustained-release granules, enteric-coated granules, liquids, eye drops, ellipsoids, emulsions, suspensions, alcohols, troches, aromatic waters, limonades, tablets, sustained-release tablets, enteric-coated tablets, sublingual tablets, hard capsules, soft capsules, sustained-release capsules, enteric capsules, pills, tinctures, soft extracts, dry extracts, fluid extracts, injections, capsules, irrigation solutions, ointments, lotions, pastes, sprays, inhalants, patches, sterile injection solutions, or aerosols, according to a conventional method, and the external preparations may have formulations such as creams, gels, patches, sprays, ointments, ointments, lotions, liniments, pastes, or cataplasmas.

[0124] Carriers, excipients and diluents that may be included in the pharmaceutical composition according to the present invention include lactose, dextrose, sucrose, oligosaccharides, 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.

[0125] When formulating, it is usually prepared using diluents or excipients such as fillers, bulking agents, binders, wetting agents, disintegrants, and surfactants.

[0126] The additives of the tablets, powders, granules, capsules, pills, and troches according to the present invention include excipients such as corn starch, potato starch, wheat starch, lactose, sucrose, glucose, fructose, D-mannitol, precipitated calcium carbonate, synthetic aluminum silicate, calcium hydrogen phosphate, calcium sulfate, sodium chloride, sodium bicarbonate, purified lanolin, microcrystalline cellulose, dextrin, sodium alginate, methylcellulose, sodium carboxymethylcellulose, kaolin, urea, colloidal silica gel, hydroxypropyl starch, hydroxypropyl methylcellulose (HPMC) 1928, HPMC 2208, HPMC 2906, HPMC 2910, propylene glycol, casein, calcium lactate, and Primogel; Gelatin, gum arabic, ethanol, agar powder, cellulose acetate phthalate, carboxymethylcellulose, calcium carboxymethylcellulose, glucose, purified water, sodium caseinate, glycerin, stearic acid, sodium carboxymethylcellulose, sodium methylcellulose, methylcellulose, microcrystalline cellulose, dextrin, hydroxycellulose, hydroxypropyl starch, hydroxymethylcellulose, refined shellac, starch starch, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, polyvinyl pyrrolidone, and binders such as hydroxypropyl methylcellulose, corn starch, agar powder, methylcellulose, bentonite, hydroxypropyl starch, sodium carboxymethylcellulose, sodium alginate, Disintegrants such as carboxymethylcellulose calcium, calcium citrate, sodium lauryl sulfate, anhydrous silicic acid, 1-hydroxypropyl cellulose, dextran, ion exchange resin, polyvinyl acetate, formaldehyde-treated casein and gelatin, alginic acid, amylose, guar gum, baking soda, polyvinylpyrrolidone, calcium phosphate, gelled starch, gum arabic, amylopectin, pectin, sodium polyphosphate, ethylcellulose, sucrose, magnesium aluminum silicate, di-sorbitol solution, and light anhydrous silicic acid;Lubricants such as calcium stearate, magnesium stearate, stearic acid, hydrogenated vegetable oil, talc, lycopodium dentata, kaolin, petrolatum, sodium stearate, cacao butter, sodium salicylate, magnesium salicylate, polyethylene glycol (PEG) 4000, PEG 6000, liquid paraffin, hydrogenated soybean oil (Lubri wax), aluminum stearate, zinc stearate, sodium lauryl sulfate, magnesium oxide, macrogol, synthetic aluminum silicate, anhydrous silicic acid, higher fatty acids, higher alcohols, silicone oil, paraffin oil, polyethylene glycol fatty acid ether, starch, sodium chloride, sodium acetate, sodium oleate, dl-leucine, and light anhydrous silicic acid can be used.

[0127] As additives of the liquid formulation according to the present invention, water, dilute hydrochloric acid, dilute sulfuric acid, sodium citrate, monostearate sucrose, polyoxyethylene sorbitol fatty acid esters (twin esters), polyoxyethylene monoalkyl ethers, lanolin ethers, lanolin esters, acetic acid, hydrochloric acid, ammonia water, ammonium carbonate, potassium hydroxide, sodium hydroxide, prolamine, polyvinylpyrrolidone, ethylcellulose, sodium carboxymethylcellulose, etc. can be used.

[0128] The syrup according to the present invention may include a solution of white sugar, other sugars, or sweeteners, and may also include a fragrance, a coloring agent, a preservative, a stabilizer, a suspending agent, an emulsifier, a viscosity modifier, and the like, as needed.

[0129] Purified water may be used in the emulsion according to the present invention, and emulsifiers, preservatives, stabilizers, fragrances, etc. may be used as needed.

[0130] The suspension according to the present invention may include suspending agents such as acacia, tragacanth, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, sodium alginate, hydroxypropylmethylcellulose (HPMC), HPMC 1828, HPMC 2906, and HPMC 2910, and surfactants, preservatives, stabilizers, colorants, and fragrances may be used as needed.

[0131] The injection according to the present invention includes a solvent such as distilled water for injection, 0.9% sodium chloride injection, Ringer's injection, dextrose injection, dextrose + sodium chloride injection, PEG, lactated Ringer's injection, ethanol, propylene glycol, non-volatile oils - sesame oil, cottonseed oil, peanut oil, soybean oil, corn oil, ethyl oleate, isopropyl myristate, and benzene benzoate; a solubilizing agent such as sodium benzoate, sodium salicylate, sodium acetate, urea, urethane, monoethylacetamide, butazolidine, propylene glycol, tween, nitrile acid amide, hexamine, and dimethylacetamide; a buffer such as weak acids and their salts (acetic acid and sodium acetate), weak bases and their salts (ammonia and ammonium acetate), organic compounds, proteins, albumin, peptone, and gums; It may include isotonic agents such as sodium chloride; stabilizers such as sodium bisulfite (NaHSO3), carbon dioxide gas, sodium metabisulfite (Na2S2O5), sodium sulfite (Na2SO3), nitrogen gas (N2), and ethylenediaminetetraacetic acid; oxidizing agents such as sodium bisulfite 0.1%, sodium formaldehyde sulfoxylate, thiourea, disodium ethylenediaminetetraacetic acid, and acetone sodium bisulfite; analgesics such as benzyl alcohol, chlorobutanol, procaine hydrochloride, glucose, and calcium gluconate; and suspending agents such as sodium cis-methylenediamine, sodium alginate, Tween 80, and aluminum monostearate.

[0132] The suppository according to the present invention comprises cocoa butter, lanolin, withepsol, polyethylene glycol, glycerogelatin, methylcellulose, carboxymethylcellulose, a mixture of stearic acid and oleic acid, Subanal, cottonseed oil, peanut oil, palm oil, cocoa butter + cholesterol, lecithin, ranet wax, glycerol monostearate, Tween or Span, Imhausen, monolene (propylene glycol monostearate), glycerin, Adeps solidus, Buytyrum Tego-G, Cebes Pharma 16, hexalide base 95, Cotomar, Hydroxocote SP, S-70-XXA, S-70-XX75 (S-70-XX95), Mechanisms such as Hydrokote 25, Hydrokote 711, Idropostal, Massa estrarium (A, AS, B, C, D, E, I, T), Massa-MF, Masupol, Masupol-15, Neosupostal-N, Paramound-B, Suposiro (OSI, OSIX, A, B, C, D, H, L), Suppository type IV (AB, B, A, BC, BBG, E, BGF, C, D, 299), Supostal (N, Es), Wecovi (W, R, S, M, Fs), Tezester triglyceride basis (TG-95, MA, 57) can be used.

[0133] Solid dosage forms for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid dosage forms are prepared by mixing the extract with at least one excipient, such as starch, calcium carbonate, sucrose or lactose, gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used.

[0134] Liquid preparations for oral administration include suspensions, solutions, emulsions, and syrups. In addition to commonly used simple diluents such as water and liquid paraffin, they may contain various excipients such as wetting agents, sweeteners, flavoring agents, and preservatives. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, and suppositories. Non-aqueous solvents and suspensions can include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.

[0135] The pharmaceutical composition according to the present invention is administered in a pharmaceutically effective amount. In the present invention, "pharmaceutically effective amount" means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment. The effective dosage level can be determined based on factors including the type and severity of the patient's disease, drug activity, drug sensitivity, administration time, administration route and excretion rate, treatment period, concurrently used drugs, and other factors well known in the medical field.

[0136] The pharmaceutical composition according to the present invention can be administered as an individual therapeutic agent or in combination with other therapeutic agents. It can be administered sequentially or simultaneously with conventional therapeutic agents, or in single or multiple doses. Taking all of the above factors into account, it is important to administer an amount that achieves maximum efficacy with minimal side effects. This amount can be readily determined by those skilled in the art to which the present invention pertains.

[0137] The pharmaceutical composition of the present invention can be administered to a subject via various routes. All modes of administration are conceivable, including oral ingestion, subcutaneous injection, intraperitoneal administration, intravenous injection, intramuscular injection, intrathecal injection, sublingual administration, buccal mucosal administration, rectal insertion, vaginal insertion, ocular administration, otic administration, nasal administration, inhalation, oral or nasal spraying, dermal administration, and transdermal administration.

[0138] The pharmaceutical composition of the present invention is determined according to the type of drug as an active ingredient, along with various related factors such as the disease to be treated, the route of administration, the patient's age, sex, weight, and the severity of the disease. Specifically, the effective dose of the composition according to the present invention may vary depending on the patient's age, sex, and weight, and is generally 0.001 to 150 mg per 1 kg of body weight, preferably 0.01 to 100 mg, administered daily or every other day, or divided into 1 to 3 times a day. However, since the dosage may increase or decrease depending on the route of administration, the severity of the disease, sex, weight, age, etc., the above dosage does not limit the scope of the present invention in any way.

[0139] In the present invention, the term "subject" means a subject requiring treatment for a disease, and more specifically, a mammal such as a human or non-human primate, mouse, rat, dog, cat, horse, and cow.

[0140] In the present invention, “administration” means providing a predetermined composition of the present invention to a subject by any appropriate method.

[0141] In the present invention, “prevention” means any action that suppresses or delays the onset of a target disease, “treatment” means any action that improves or beneficially changes a target disease and its metabolic abnormality symptoms by administering a pharmaceutical composition according to the present invention, and “improvement” means any action that reduces a parameter related to a target disease, for example, the severity of a symptom, by administering a composition according to the present invention.

[0142]

[0143] In addition, the present invention provides a kit for preventing or treating breast cancer, comprising a pharmaceutical composition according to the present invention and an instruction manual.

[0144] The kit according to the present invention may include, without limitation, other components, compositions, solutions, devices, etc. commonly required for the prevention or treatment of breast cancer, in addition to the above compounds and anticancer agents, and in particular, may include instructions for the appropriate use and storage of the compounds according to the present invention. All components included in the kit may be used one or more times without limitation, there is no restriction on the order in which each substance is used, and the application of each substance may be carried out simultaneously or microscopically.

[0145] In addition, the kit of the present invention may include a container in addition to the compound and anticancer agent. The container may serve to package the composition, and may also serve to store and fix the composition. The material of the container may take the form of, for example, a bottle, a tub, a sachet, an envelope, a tube, an ampoule, etc., and these may be formed partially or wholly from plastic, glass, paper, foil, wax, etc. The container may be initially equipped with a completely or partially detachable stopper that is part of the container or can be mechanically, adhesively, or other means attached to the container, and may also be equipped with a stopper that allows access to the contents by a syringe needle. The kit may include an outer package, and the outer package may include, but is not limited to, instructions for the use of the components.

[0146]

[0147] In this specification, “active ingredient” means an ingredient that exhibits the intended activity alone or can exhibit the intended activity together with a carrier or the like that is inactive in itself.

[0148] Terms or words used in this specification and claims should not be interpreted as limited to their usual or dictionary meanings, but should be interpreted as meanings and concepts that conform to the technical idea of ​​the present invention, based on the principle that the inventor can appropriately define the concept of the term to explain his or her own invention in the best way.

[0149]

[0150] Hereinafter, preferred examples are presented to aid in understanding the present invention. However, the following examples are provided solely to facilitate a better understanding of the present invention, and the scope of the present invention is not limited by the following examples.

[0151]

[0152] [Example]

[0153] Example 1. Synthesis of compound AON-MG23 of the present invention

[0154] <Step 1> Synthesis of N-cyclopropyl-N-(2-nitrophenyl)methanesulfonamide

[0155] [Reaction Formula 1]

[0156]

[0157] 1-Fluoro-2-nitrobenzene (1.00 eq) and cyclopropyl amine (1.00 eq) were dissolved in acetonitrile (ACN), and methanesulfonyl chloride (MsCl, 1.0 eq) was slowly added at 0°C, followed by stirring at the same temperature for 1 hour. Then, cesium carbonate (Cs2CO3, 5.00 eq) was added at the same temperature, refluxed, and stirred overnight. After completion of the reaction, the temperature was lowered to room temperature, and ethyl acetate and water were used for extraction. Anhydrous sodium sulfate was added to the organic layer, stirred, filtered, and the filtrate was concentrated under reduced pressure. The concentrated residue was purified by column chromatography (hexane: ethyl acetate = 3:1) to synthesize N-cyclopropyl-N-(2-nitrophenyl)methanesulfonamide as a light yellow solid, with a yield of 36%.

[0158]

[0159] <Step 2> Synthesis of N-(2-aminophenyl)-N-cyclopropylmethanesulfonamide

[0160] [Reaction Formula 2]

[0161]

[0162] N-Cyclopropyl-N-(2-nitrophenyl)methanesulfonamide (1.00 eq) synthesized in Step 1 was added to 1,4-dioxane and water (3:1) and stirred, then the reactor was cooled to 0°C, and zinc (Zn, 10.0 eq) and ammonium chloride (NH4Cl, 10.0 eq) were added. Then, the temperature was gradually increased and the mixture was stirred for 4 hours. After completion of the reaction, the mixture was filtered using Celite, and the filtrate was extracted with ethyl acetate and water. The organic layer was added to anhydrous sodium sulfate, stirred, filtered using a filter, and the filtrate was concentrated under reduced pressure. The concentrated residue was used in Step 3 without any additional purification.

[0163]

[0164] <Step 3> Synthesis of N-cyclopropyl-N-(2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)methanesulfonamide

[0165] [Reaction Formula 3]

[0166]

[0167] N-(2-Aminophenyl)-N-cyclopropylmethanesulfonamide (1.00 eq) synthesized in Step 2 was added to isopropyl alcohol (IPA), and 2,4,5-trichloropyrimidine (1.1 eq) and N,N-diisopropylethylamine (DIPEA, 2.5 eq) were added at room temperature. The mixture was refluxed and stirred overnight. After completion of the reaction, the mixture was evaporated under reduced pressure, and extracted with water and dichloromethane. The organic layer was washed with 2 N hydrochloric acid (HCl), and anhydrous sodium sulfate was added to the organic layer and stirred. Then, the mixture was filtered using a filter, and the filtrate was concentrated under reduced pressure. The concentrated residue was purified by column chromatography (hexane:ethyl acetate = 3:1) to synthesize N-cyclopropyl-N-(2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)methanesulfonamide as a light yellow solid, with a yield of 58.9%.

[0168]

[0169] <Step 4> Synthesis of N-(2-((5-chloro-2-((4-(4-(dimethylamino)piperidin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-cyclopropylmethanesulfonamide

[0170] [Reaction Formula 4]

[0171]

[0172] N-Cyclopropyl-N-(2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)methanesulfonamide (1.00 eq) synthesized in Step 3 was added to ethanol (EtOH), and 1-(4-amino-3-methoxyphenyl)-N,N-dimethylpiperidin-4-amine (1.00 eq) and trifluoroacetic acid (TFA, 1.95 eq) were added at room temperature, followed by reflux and stirring overnight. After completion of the reaction, the mixture was neutralized with 1 N sodium hydroxide (NaOH) solution and extracted with water and ethyl acetate. The organic layer was added with anhydrous sodium sulfate, stirred, filtered using a filter, and the filtrate was concentrated under reduced pressure. The concentrated residue was purified by column chromatography (hexane:ethyl acetate = 3:1) to synthesize N-(2-((5-chloro-2-((4-(4-(dimethylamino)piperidin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-cyclopropylmethanesulfonamide [N-(2-((5-chloro-2-((4-(4-(dimethylamino)piperidin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-cyclopropylmethanesulfonamide](AON-MG23) as a yellow solid, and the yield was 25%.

[0173] 1H NMR (500 MHz, DMSO-d6) δ 8.33 (s, 1H), 8.19 (s, 1H), 8.09 (s, 1H), 7.99 (s, 1H), 7.62 (dd, J = 7.8, 1.6 Hz, 1H), 7.35 (d, J = 8.7 Hz, 1H), 7.22 (d, J = 8.1 Hz, 1H), 7.15 (td, J = 7.6, 1.6 Hz, 1H), 6.63 (d, J = 2.5 Hz, 1H), 6.48 (dd, J = 8.7, 2.5 Hz, 1H), 3.75 (s, 3H), 3.72 (d, J = 12.2 Hz, 2H), 3.23 (m, 4H), 2.68 (td, J = 12.1, 2.5 Hz, 2H), 2.22 (s, 6H), 1.86 (d, J = 12.4 Hz, 2H), 1.51 (qd, J = 12.0, 3.9 Hz, 2H), 1.04 - 0.92 (m, 2H), 0.55 - 0.49 (m, 1H), 0.17 - 0.14 (m, 1H). HRMS: 585.2294, cal: 585.2289.

[0174]

[0175] Example 2. Confirmation of the proliferation inhibitory effect of the compound AON-MG23 of the present invention on breast cancer cells.

[0176] 1X10 human breast cancer cell line MDA-MB-231 cells were seeded in a 96-well plate 5 After seeding at a density of 10 cells / well and culturing for 24 hours, the compound AON-MG23 of the present invention was treated at various concentrations and then cultured for 48 hours. The compound of the present invention was treated at various concentrations of 0 μM, 0.1 μM, 0.25 μM, 0.5 μM, 1 μM, 2 μM, 4 μM, 8 μM, and 16 μM. 10 μl of CCK reagent was added, reacted for 1 hour, and then measured at 450 nm absorbance.

[0177] As a result, as shown in Fig. 1, it was confirmed that the compound AON-MG23 of the present invention inhibits the proliferation of breast cancer cells.

[0178]

[0179] Example 3. Confirmation of the proliferation inhibitory effect of the compound AON-MG23 of the present invention on breast cancer cells.

[0180] To confirm the proliferation inhibitory effect of the compound of the present invention on breast cancer cells, a cluster formation test was conducted. Specifically, six breast cancer cell lines (SUM149, BCX010, BT20, MDA-MB-231-LM3, CAL51, PyMT-N) were seeded in 6-well cell culture plates at 250 or 1,000 cells per well. The following day, the cell culture medium was removed and replaced with a cell culture medium containing the compound of the present invention, AON-MG23, at concentrations of 0 μM, 0.25 μM, 0.5 μM, and 1 μM. After culturing the cells for 11 to 14 days, the formed cell clusters were stained and photographed, and the number of cell clusters was measured and analyzed using Image J software.

[0181] As a result, as shown in Figures 2a to 2c, it was confirmed that cell cluster formation was inhibited in all six breast cancer cell lines after treatment with the compound AON-MG23 of the present invention.

[0182]

[0183] Example 4. Confirmation of the carcinogenic inhibitory effect of the compound AON-MG23 of the present invention on breast cancer cells.

[0184] In order to confirm the carcinogenic inhibitory effect of the compound of the present invention on breast cancer cells, an anchorage-dependent soft agar assay was performed. Specifically, 0.5% agar and 0.7% agar were added to cell culture media in which the compound of the present invention was diluted to concentrations of 0 nM, 100 nM, 500 nM, and 1000 nM, respectively, and prepared. 2 ml of 0.5% agar containing the compound of the present invention at different concentrations prepared in a 6-well cell culture plate was added and solidified at room temperature, and 1x10 of four breast cancer cell lines (SUM149, BCX010, BT20, MDA-MB-231-LM3) were inoculated. 4 1 ml of cells and 1 ml of 0.7% agar containing the compound of the present invention at various concentrations were mixed in a 1:1 ratio to make 0.35%, 2 ml of which was added onto the solidified 0.5% agar, and the mixture was allowed to solidify at room temperature until the upper layer was fixed, and then cultured in a 37°C, 5% CO2 incubator for 2 weeks. The formed cell clones were stained, photographed, and the number of cell clones was measured and analyzed using Image J software.

[0185] As a result, as shown in Figures 3a and 3b, it was confirmed that the compound AON-MG23 of the present invention inhibited the carcinogenicity of four types of breast cancer cells starting from 100 nM.

[0186]

[0187] Example 5. Confirmation of the cell migration inhibitory effect of the compound AON-MG23 of the present invention on breast cancer cells.

[0188] MDA-MB-231 cells, a human breast cancer cell line, were plated on SPLScar Block (SPL) plates at 7X10 4 / well and cultured for 24 hours. After 20 hours, the block was removed and the compound AON-MG23 of the present invention was treated at various concentrations, and cultured for 24 hours at 37°C in a CO2 incubator. The compound of the present invention was treated at various concentrations of 0 μM, 0.5 μM, 1 μM, 2 μM, and 4 μM. Pictures were taken before and after culture, and the distance of cell migration was measured using Image J software. Based on the results, an analysis was conducted to see if cell migration was inhibited.

[0189] As a result, as shown in Fig. 4, it was confirmed that when the compound of the present invention was treated at a concentration of 0.5 μM, MDA-MB-231 cell migration was inhibited by 50% compared to the control group.

[0190]

[0191] Example 6. Confirmation of the cell migration inhibitory effect of the compound AON-MG23 of the present invention on breast cancer cells.

[0192] Cells pretreated with 0.5 μM of the compound AON-MG23 of the present invention and untreated cells were prepared for the breast cancer cell line MDA-MG231-LM3, and as shown in Fig. 5, 6x10 of both the untreated group and the pretreated group were seeded in a cell culture medium containing no 5% fetal bovine serum (FBS) on top of a membrane filter (Transwell membrane insert, Corning). 4 The membrane filter seeded with cells was placed in a 24-well plate containing cell culture medium containing fetal bovine serum and cultured for 8 hours in a 37°C, 5% CO2 incubator. The cells that migrated to the lower surface of the membrane filter were stained and photographed under a microscope, and the number of migrated cells was measured and analyzed using Image J software.

[0193] As a result, as shown in Fig. 6, it was confirmed that cell migration was inhibited in the group pretreated with the compound AON-MG23 of the present invention compared to the untreated group.

[0194]

[0195] Example 7. Confirmation of the breast cancer cell metastasis inhibition effect of the compound AON-MG23 of the present invention.

[0196] Human breast cancer cell line MDA MB-231 cells were seeded on top of Matrigel-coated filters (Transwell invasion chambers, Corning) at a density of 6X10 4 After seeding at a density of 10 cells / well, the cells were treated with the compound AON-MG23 of the present invention (0, 0.5, 1, 2, 4 μM) and cultured at 37°C in a CO2 incubator for 20 hours. After culture, cells were fixed and stained using the Diff-Quick Stain Kit (Sysmex, Kobe, Japan). Images of the stained cells were captured under a microscope, and the cells were counted using Image J software, followed by statistical analysis.

[0197] As a result, as shown in Fig. 7, it was confirmed that the group treated with the compound AON-MG23 of the present invention had a reduced degree of penetration into the matrix gel compared to the untreated control group, thereby suppressing the metastatic ability of cancer cells.

[0198]

[0199] Example 8. Confirmation of the breast cancer cell metastasis inhibition effect of the compound AON-MG23 of the present invention.

[0200] Breast cancer cell line MDA-MB-231 was cultured on top of a Matrigel-coated membrane filter (Transwell membrane insert, Corning) at 6X10 4After seeding at a density of 10 cells / well, the compound AON-MG23 of the present invention was treated to the cells at concentrations of 0 μM (DMSO), 0.5 μM, and 1 μM, and cultured at 37°C in a CO2 incubator for 24 hours. After 24 hours of culture, the cells on the underside of the membrane filter were stained, photographed under a microscope, and counted and analyzed using Image J software.

[0201] As a result, as shown in Fig. 8, the experimental group treated with the compound AON-MG23 of the present invention showed a decrease in the degree of matrigel penetration compared to the untreated control group, and it was confirmed that the decrease in the degree of matrigel penetration was dependent on the AON-MG23 treatment concentration.

[0202]

[0203] Example 9. Confirmation of the effect of the compound AON-MG23 of the present invention on the expression of ANO1 and EGFR proteins in human breast cancer cell lines.

[0204] 5X10 human breast cancer cell line MDA-MB-231 in a 60 mm dish 5After seeding at a density of 10 cells / dish and culturing for 24 hours, the compound AON-MG23 of the present invention was treated at concentrations of 0.125 μM, 0.25 μM, 0.5 μM, 1 μM, and 2 μM, and the untreated control group was treated with DMSO and cultured for 48 hours. The cultured cells were harvested and lysed for Western blotting. Antibodies for Western blotting included anti-ANO1 antibody (Abcam, ab53212), anti-EGFR antibody (Cell Signaling, #4267S), and anti-GAPDH antibody (Cell Signaling, #5174), and the protein concentration was quantified using the BSA method (Protein Quantitation Assay, Bovine serum albumin assay) (Pierce, Cat. 23225). After lysing the cells, the same amount (20 μg) of protein obtained therefrom was subjected to SDS-PAGE to separate the proteins by molecular weight, transferred to a polyvinylidene fluoride membrane (PVDF, Bio-rad), and treated with 5% blocking buffer (5% Skim milk in TBS-T, Tris-buffered saline buffer containing 0.1% Tween 20) at room temperature for 1 hour. Next, the membrane was treated with the primary antibody and reacted at 4°C for 18 hours. After the reaction, the membrane was washed three times for 10 minutes each with TBS-T at room temperature. Subsequently, the membrane was reacted with the secondary antibody labeled with horseradish peroxidase at room temperature for 1 hour, and then washed three times for 10 minutes each with TBS-T. After washing, the membrane was treated with an ECL kit (Thermo, West Pico Plus) for reaction and visualized using a da Vinci-Q (Youngin Lab Plus) device. The visualized results were analyzed by quantifying the amount of each protein using Image J software.

[0205] As a result, as shown in FIG. 9, the compound AON-MG23 of the present invention reduced both the ANO1 protein and the EGFR protein of breast cancer cell lines, and it was confirmed that the protein was degraded from the 1 μM treatment group for the EGFR protein and from the 0.5 μM treatment group for the ANO1 protein.

[0206]

[0207] Example 10. Confirmation of the drug combination effect of the compound AON-MG23 of the present invention on human breast cancer cells.

[0208] The combined effect of the compound AON-MG23 of the present invention was confirmed using the Bliss scoring model of the results of the sulfur rhodamine B assay (SRB assay). Specifically, 1x10 human breast cancer cell lines SUM149 and HCC1806 were seeded in a 96-well cell culture plate. 3Cells were seeded at a density of 10 cells / well. The next day, the compound AON-MG23 of the present invention and the drug Paclitaxel, whose combined effect is to be confirmed, were diluted to the concentration to be tested, and the cell culture medium cultured for 24 hours was carefully removed, and AON-MG23 and Paclitaxel were treated together at different concentrations and cultured for 5 days. After 5 days of combined treatment, the culture medium containing the drugs was removed, 10% TCA (Trichloroacetic acid) was added to each well, fixed for 1 hour at 4°C, TCA was removed, and the 96-well plate was washed 5 times with running water and dried at room temperature for 1 hour. Then, 0.4% SRB solution (Sulphorhodamine B in 1% acetic acid) was added to each well and stained for 30 minutes at room temperature. After removing the 0.4% SRB solution, the wells were washed five times with 1% acetic acid and dried for 1 hour. After drying, 200 μL of 10 mM Tris-base (pH 10.5) was added to each well and the stained dye was dissolved with stirring for 10 minutes at room temperature. The absorbance of the dissolved solution was measured at 540 nM using a plate reader, and the measured absorbance values ​​were converted to percentages compared to the control group and saved in Excel file format. After accessing https: / synergyfinder.fimm.fi / , the percentageized Excel file was uploaded and the degree of synergistic effect when the drugs were combined was analyzed. The presence of a synergistic effect was evaluated according to the following criteria with reference to related literature (Bliss, CI (1939). The toxicity of poisons applied jointly. Annals of Applied Biology, 26(3), 585-615.): If the score > 0, there is a synergistic effect, if the score = 0, there is an independent effect, and if the score < 0, there is an antagonistic effect.

[0209] As shown in FIGS. 10a and 10b, the Bliss synergy score analysis of the compound AON-MG23 of the present invention and Paclitaxel in human breast cancer cell lines SUM149 and HCC1806 confirmed a high synergistic effect with a score of 18.743 in the SUM149 cell line and 9.249 in the HCC1806 cell line.

[0210]

[0211] The foregoing description of the present invention is provided for illustrative purposes only. Those skilled in the art will readily appreciate that the present invention can be readily modified into other specific forms without altering the technical spirit or essential characteristics of the present invention. Therefore, the embodiments described above should be understood as illustrative in all respects and not restrictive.

[0212]

[0213] The novel compound of the present invention not only significantly inhibits the growth, proliferation, migration, carcinogenesis, and metastasis of breast cancer cells, but also simultaneously inhibits ANO1 and EGFR in breast cancer cells, thereby exhibiting a more potent anticancer effect through dual inhibition of the two proteins. Furthermore, when used in combination with anticancer drugs, the efficacy of the anticancer drugs can be further enhanced and cancer resistance can be suppressed. Therefore, the compound can be used as a dual-target anticancer drug of ANO1 and EGFR on its own, and can also be utilized as a combination agent of anticancer drugs, and thus has industrial applicability as it can be utilized in various fields of prevention and treatment of breast cancer.

Claims

1. A pharmaceutical composition for preventing or treating breast cancer, comprising a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. [Chemical Formula 1] 2. In paragraph 1, A pharmaceutical composition for preventing or treating breast cancer, characterized in that the compound or a pharmaceutically acceptable salt thereof simultaneously inhibits EGFR and ANO1.

3. In paragraph 1, A pharmaceutical composition for preventing or treating breast cancer, wherein the compound or a pharmaceutically acceptable salt thereof satisfies one or more characteristics selected from the group consisting of: (a) inhibiting the proliferation or growth of cancer cells; (b) inhibiting the migration of cancer cells; (c) inhibiting the tumorigenicity of cancer cells; (d) inhibiting cancer metastasis; and (e) Inhibits cancer resistance to anticancer drugs.

4. In paragraph 3, A pharmaceutical composition for preventing or treating breast cancer, characterized in that the anticancer agent is a chemotherapy anticancer agent or a targeted anticancer agent.

5. In paragraph 4, A pharmaceutical composition for preventing or treating breast cancer, characterized in that the chemotherapeutic agent is at least one selected from the group consisting of paclitaxel, docetaxel, dactinomycin, doxorubicin, daunorubicin, mitomycin, and bleomycin.

6. In paragraph 4, A pharmaceutical composition for preventing or treating breast cancer, characterized in that the targeted anticancer agent is at least one selected from the group consisting of a targeted anticancer agent for EGFR, a targeted anticancer agent for TROP-2, and a targeted anticancer agent for PARP.

7. In paragraph 1, A pharmaceutical composition for preventing or treating breast cancer, characterized in that the breast cancer is at least one selected from the group consisting of breast intraepithelial carcinoma, inflammatory breast cancer, triple-negative breast cancer, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ (non-invasive), lobular carcinoma in situ (non-invasive), Paget's disease of the breast, invasive breast cancer, and metastatic breast cancer.

8. In paragraph 1, A pharmaceutical composition for preventing or treating breast cancer, characterized in that the pharmaceutical composition is administered in combination with a chemotherapeutic agent or a targeted anticancer agent.

9. In paragraph 8, A pharmaceutical composition for preventing or treating breast cancer, characterized in that the pharmaceutical composition is administered simultaneously, separately, or sequentially with the anticancer agent. 10.(i) A compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof; and (ii) A pharmaceutical composition for preventing or treating breast cancer, comprising as an active ingredient at least one anticancer agent selected from the group consisting of chemotherapeutic anticancer agents and targeted anticancer agents. [Chemical Formula 1] 11. In paragraph 10, A pharmaceutical composition for preventing or treating breast cancer, wherein the compound or a pharmaceutically acceptable salt thereof suppresses the resistance of cancer cells to the anticancer agent.

12. In paragraph 10, A pharmaceutical composition for preventing or treating breast cancer, characterized in that the composition is in the form of a mixture comprising the compound or a pharmaceutically acceptable salt thereof; and the anticancer agent.

13. In paragraph 10, A pharmaceutical composition for preventing or treating breast cancer, characterized in that the composition is in a form in which the compound or a pharmaceutically acceptable salt thereof and an anticancer agent are each formulated and administered simultaneously, separately, or sequentially.

14. A pharmaceutical composition for enhancing the anticancer effect of an anticancer agent for breast cancer, comprising a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. [Chemical Formula 1] 15. In paragraph 14, A pharmaceutical composition for enhancing the anticancer effect of an anticancer agent for breast cancer, characterized in that the anticancer agent is at least one selected from the group consisting of a chemotherapy anticancer agent and a targeted anticancer agent.

16. In paragraph 15, A pharmaceutical composition for enhancing the anticancer effect of an anticancer agent for breast cancer, characterized in that the chemotherapeutic agent is at least one selected from the group consisting of paclitaxel, docetaxel, dactinomycin, doxorubicin, daunorubicin, mitomycin, and bleomycin.

17. In paragraph 15, A pharmaceutical composition for enhancing the anticancer effect of an anticancer agent for breast cancer, characterized in that the targeted anticancer agent is at least one selected from the group consisting of a targeted anticancer agent for EGFR, a targeted anticancer agent for TROP-2, and a targeted anticancer agent for PARP.

18. In paragraph 14, A pharmaceutical composition for enhancing the anticancer effect of an anticancer agent for breast cancer, characterized in that the composition is administered simultaneously with, separately from, or sequentially with the anticancer agent.

19. A method for preventing, improving, or treating breast cancer, comprising administering to a subject in need thereof a pharmaceutically effective amount of a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof; or a composition containing the same. [Chemical Formula 1] 20. Use of a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof; or a composition containing the same, for preventing, improving, or treating breast cancer. [Chemical Formula 1] 21. Use of a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof; or a composition containing the same, for producing a preparation for preventing, improving, or treating breast cancer. [Chemical Formula 1] 22. A method for enhancing the anticancer effect of an anticancer agent for breast cancer, comprising a step of administering a pharmaceutically effective amount of a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof; or a composition containing the same, to a subject in need thereof. [Chemical Formula 1] 23. Use of a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof; or a composition containing the same, for enhancing the anticancer effect of an anticancer agent for breast cancer. [Chemical Formula 1] 24. Use for producing a preparation for enhancing the anticancer effect of an anticancer agent against breast cancer, comprising a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof; or a composition containing the same. [Chemical Formula 1] 25. A method for preventing, improving, or treating breast cancer, comprising administering to a subject in need thereof a pharmaceutically effective amount of (i) a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof, and (ii) at least one anticancer agent selected from the group consisting of chemotherapeutic agents and targeted anticancer agents; or a composition containing them. [Chemical Formula 1] 26.(i) A compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof, and (ii) at least one anticancer agent selected from the group consisting of chemotherapeutic anticancer agents and targeted anticancer agents; or a composition containing them for use in preventing, improving, or treating breast cancer. [Chemical Formula 1] 27. (i) A compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof, and (ii) at least one anticancer agent selected from the group consisting of chemotherapeutic anticancer agents and targeted anticancer agents; or a composition containing them, for producing a preparation for preventing, improving, or treating breast cancer. [Chemical Formula 1]

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