Pharmaceutical composition for preventing or treating breast cancer

Abstract

This invention relates to the use of novel compounds for the prevention, mitigation, or treatment of breast cancer. These novel compounds not only significantly inhibit the growth, proliferation, migration, carcinogenesis, and metastasis of breast cancer cells, but also simultaneously inhibit ANO1 and EGFR in breast cancer cells, thereby exhibiting a stronger anti-cancer effect through the dual inhibition of these two proteins. Furthermore, when used in combination with anticancer agents, these compounds can further enhance the efficacy of the anticancer agents and inhibit drug resistance in the cancer. Therefore, these compounds can be used on their own as dual-target anticancer agents against ANO1 and EGFR, and also as combination formulations of anticancer agents, thus holding promise for various applications in the prevention and treatment of breast cancer.

Description

Technical Field

[0001] This invention relates to the use of novel compounds for the prevention, improvement or treatment of breast cancer.

[0002] This application claims priority and benefit to Korean Patent Application No. 10-2023-0162398, filed on November 21, 2023, and Korean Patent Application No. 10-2024-0166743, filed on November 20, 2024, the disclosure of which is incorporated herein by reference in its entirety. Background Technology

[0003] Breast cancer refers to cancer originating in the lactiferous ducts and lobules of the breast. Currently, various factors such as estrogen administration, family history, medical history, childbirth history, and dietary habits are being discussed as causes of breast cancer, but none has been definitively identified. The incidence of breast cancer among modern women is rapidly increasing, and factors such as low birth rates, short breastfeeding periods, early menarche, and late menopause are also increasing the incidence in women in their 20s and 30s.

[0004] Clinically, breast cancer is divided into three subgroups based on the presence or absence of expression of major genes: 1) estrogen receptor (ER) positive, which expresses estrogen receptor; 2) human epidermal growth factor receptor 2 (HER2) positive, which expresses HER2; and 3) triple-negative breast cancer, which does not express any of the three genes: ER, progesterone receptor (PR), and HER2.

[0005] Epidermal growth factor receptor (EGFR) is the receptor for epidermal growth factor (EGF), a peptide that promotes the growth of breast cancer cells and is present on both the inner and outer layers of the cell membrane. EGFR promotes cell growth and DNA synthesis by activating EGF, transforming growth factor α, and tyrosine kinases. The presence of EGFR has been observed not only in breast cancer but also in lung, gastric, and liver cancers. In particular, EGFR is known to play a crucial role in oncogenicity and tumor progression in breast cancer. Regarding the prognosis of breast cancer, EGFR expression is closely related to histological grade and lymph node invasion, and EGFR-positive breast cancer is known to have higher recurrence and mortality rates compared to EGFR-negative breast cancer.

[0006] Meanwhile, calcium-activated chloride channels (CaCCs) 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 signal transduction, and cell growth. Since the identification of calcium-activated chloride channel-1 (anoctamin-1) / transmembrane protein 16 (ANO1 / TMEM16A) as a CaCC in 2008, various studies have shown that anoctamin-1 (ANO1) is highly expressed in bronchial, intestinal, glandular epithelial, smooth muscle, intestinal pacemaker cells, sensory nerves, and various types of tumor cells such as head and neck cancer, breast cancer, prostate cancer, and kidney cancer, and that ANO1 has multiple physiological functions.

[0007] ANO1 is located on chromosome 11q13 and is overexpressed in various cancer cells, such as head and neck cancer, breast cancer, and prostate cancer. Recent studies have revealed ANO1's involvement in cell growth, migration, carcinogenesis, and cancer development. For example, in mouse models, inhibition of ANO1 expression in prostate cancer cells (PC3) has been observed to suppress cell growth, metastasis, invasion, and tumor development, and the ANO1 inhibitor T16Ainh-A01 has inhibited the growth of Cajal stromal cells (ICC) and pancreatic cancer cells (CFPAC1) that highly express ANO1. Furthermore, inhibition of ANO1 expression in breast cancer cells has been reported to suppress cell growth, induce apoptosis, and inhibit tumor growth in xenograft models. Additionally, inhibition of ANO1 has been found to exert anticancer effects by inhibiting EGFR and calmodulin-dependent protein kinase 2 (CAMK2) signaling in head and neck cancer (head and neck squamous cell carcinoma (HNSCC)), esophageal squamous cell carcinoma (ESCC), and breast cancer cells. Therefore, recent research results suggest that pharmacological inhibition of ANO1 ion channel activity has the potential to treat head and neck cancer, esophageal cancer, gastrointestinal cancer, breast cancer, and prostate cancer that overexpress ANO1.

[0008] Therefore, both ANO1 and EGFR proteins have the potential to be therapeutic targets for breast cancer. However, no substance has yet been found that can exhibit excellent anti-cancer effects through the dual inhibition of ANO1 and EGFR. Summary of the Invention

[0009] Technical issues The inventors completed this invention by confirming that the novel compound of this invention inhibits the growth, proliferation, migration, tumorigenesis and metastasis of breast cancer cells, while simultaneously inhibiting ANO1, a calcium-dependent chloride ion channel, and EGFR, an epidermal growth factor receptor. This not only demonstrates excellent anti-cancer effects, but also exhibits high synergistic effects when co-administered with anticancer agents.

[0010] Therefore, one object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of breast cancer, comprising, as an active ingredient, a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof.

[0011] [Chemical Formula 1] Another object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of breast cancer, comprising as an active ingredient (i) a compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof; and (ii) one or more anticancer agents selected from the group consisting of chemical anticancer agents and targeted anticancer agents.

[0012] Another object of the present invention is to provide a pharmaceutical composition for enhancing the anticancer effect of anticancer agents on breast cancer, comprising a compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0013] However, the technical problems to be solved in this invention are not limited to those described above, and other problems not described herein will be fully understood by those skilled in the art from the following description.

[0014] Technical solution To achieve the above objectives, the present invention provides a pharmaceutical composition for the prevention or treatment of breast cancer, comprising, as an active ingredient, a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof.

[0015] [Chemical Formula 1] In one embodiment of the present invention, the breast cancer may be one or more selected from the group consisting of ductal carcinoma in situ, 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.

[0016] In another embodiment of the invention, the compound or a pharmaceutically acceptable salt thereof may simultaneously inhibit epidermal growth factor receptor (EGFR) and anoctamin-1 (ANO1), but is not limited thereto.

[0017] In another embodiment of the invention, the compound or a pharmaceutically acceptable salt thereof may satisfy one or more properties selected from the group consisting of, but is not limited thereto: (a) Inhibits the proliferation or growth of cancer cells; (b) Inhibits the migration of cancer cells; (c) Inhibits the tumorigenicity of cancer cells; (d) Inhibit cancer metastasis; and (e) Inhibit cancer resistance to anticancer agents.

[0018] In another embodiment of the present invention, the anticancer agent may be a chemoanticancer agent or a targeted anticancer agent, but is not limited thereto.

[0019] In another embodiment of the present invention, the chemical anticancer agent may be one or more selected from the group consisting of paclitaxel, docetaxel, actinomycin D, doxorubicin, daunorubicin, mitomycin and bleomycin, but is not limited thereto.

[0020] In another embodiment of the present invention, the targeted anticancer agent may be one or more selected from the group consisting of EGFR targeted anticancer agents, trophoblast surface antigen 2 (TROP-2) targeted anticancer agents and poly(ADP-ribose) polymerase (PARP) targeted anticancer agents, but is not limited thereto.

[0021] In another embodiment of the invention, the pharmaceutical composition may be administered in combination with a chemoanticancer agent or a targeted anticancer agent, but is not limited thereto.

[0022] In another embodiment of the present invention, the pharmaceutical composition may be administered simultaneously, separately, or sequentially with the anticancer agent, but is not limited thereto.

[0023] In addition, the present invention provides a pharmaceutical composition for the prevention or treatment of breast cancer, comprising as an active ingredient (i) a compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof; and (ii) one or more anticancer agents selected from the group consisting of chemical anticancer agents and targeted anticancer agents.

[0024] In one embodiment of the invention, the compound or a pharmaceutically acceptable salt thereof may inhibit cancer cells’ resistance to the anticancer agent, but is not limited thereto.

[0025] In another embodiment of the invention, the composition may be in the form of a mixture of the compound or a pharmaceutically acceptable salt thereof and the anticancer agent, but is not limited thereto.

[0026] In another embodiment of the 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 for simultaneous, separate or sequential administration, but is not limited thereto.

[0027] In addition, the present invention provides a pharmaceutical composition for enhancing the anticancer effect of anticancer agents on breast cancer, comprising a compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0028] In one embodiment of the present invention, the anticancer agent may be one or more selected from the group consisting of chemical anticancer agents and targeted anticancer agents, but is not limited thereto.

[0029] In another embodiment of the present invention, the chemical anticancer agent may be one or more selected from the group consisting of paclitaxel, docetaxel, actinomycin D, doxorubicin, daunorubicin, mitomycin and bleomycin, but is not limited thereto.

[0030] In another embodiment of the present invention, the targeted anticancer agent may be one or more selected from the group consisting of EGFR-targeted anticancer agents, TROP-2-targeted anticancer agents and PARP-targeted anticancer agents, but is not limited thereto.

[0031] In another embodiment of the invention, the composition may be administered simultaneously, separately, or sequentially with the anticancer agent, but is not limited thereto.

[0032] In addition, the present invention provides a method for preventing, improving or treating breast cancer, or a method for enhancing the anticancer effect of an anticancer agent on breast cancer, comprising administering to a subject in need a pharmaceutically effective amount of a compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof; or a composition comprising the compound or a pharmaceutically acceptable salt thereof.

[0033] In addition, the present invention provides the use of a compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof; or a composition comprising the compound or a pharmaceutically acceptable salt thereof for the prevention, improvement or treatment of breast cancer; or for the enhancement of the anticancer effect of an anticancer agent on breast cancer.

[0034] Additionally, the present invention provides the use of a compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof; or a composition comprising the compound or a pharmaceutically acceptable salt thereof for the preparation of an agent for the prevention, improvement or treatment of breast cancer; or for the preparation of an agent for enhancing the anticancer effect of an anticancer agent on breast cancer.

[0035] In addition, the present invention provides a method for preventing, improving or treating breast cancer, comprising administering to a subject in need of the following in a pharmaceutically effective amount: (i) a compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof, and (ii) one or more anticancer agents selected from the group consisting of chemical anticancer agents and targeted anticancer agents; or a composition comprising the compound or a pharmaceutically acceptable salt thereof and said one or more anticancer agents.

[0036] Additionally, the present invention provides (i) a compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof, and (ii) one or more anticancer agents selected from the group consisting of chemical anticancer agents and targeted anticancer agents; or the use of a composition comprising the compound or a pharmaceutically acceptable salt thereof and said one or more anticancer agents for the prevention, improvement or treatment of breast cancer.

[0037] Additionally, the present invention provides (i) a compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof, and (ii) one or more anticancer agents selected from the group consisting of chemical anticancer agents and targeted anticancer agents; or the use of a composition comprising the compound or a pharmaceutically acceptable salt thereof and said one or more anticancer agents for the preparation of an agent for the prevention, improvement or treatment of breast cancer.

[0038] Beneficial effects The novel compound of this invention not only significantly inhibits the growth, proliferation, migration, tumorigenesis, and metastasis of breast cancer cells, but also simultaneously inhibits ANO1 and EGFR in breast cancer cells, thereby exhibiting a stronger anti-cancer effect through the dual inhibition of these two proteins. Furthermore, when used in combination with anticancer agents, this compound can further enhance the efficacy of the anticancer agents and inhibit cancer drug resistance. Therefore, this compound can be used on its own as a dual-target anticancer agent against ANO1 and EGFR, and can also be used as a combination formulation with anticancer agents, thus it is expected to be utilized in various ways in the prevention and treatment of breast cancer. Attached Figure Description

[0039] Figure 1 The results of CCK assays performed after treating human breast cancer cell line MDA-MB-231 cells with various concentrations of the compound AON-MG23 of the present invention to confirm its inhibitory effect on the proliferation of human breast cancer cells are shown.

[0040] Figures 2A to 2C The results show the results of confirming the inhibitory effect of the compound AON-MG23 of the present invention on the proliferation of human breast cancer cells, and confirming the cell colony-forming ability after treating six breast cancer cell lines (SUM149, BCX010, BT20, MDA-MB-231-LM3, CAL51 and PyMT-N) with various concentrations of the compound AON-MG23 of the present invention.

[0041] Figure 3A and Figure 3B The results of an anchorage-independent soft agar assay are shown to confirm the tumorigenic inhibitory effect of the compound AON-MG23 of the present invention on human breast cancer cells. The assay was performed after treating four breast cancer cell lines (SUM149, BCX010, BT20, and MDA-MB-231-LM3) with various concentrations of the compound AON-MG23 of the present invention.

[0042] Figure 4The results show the effects of the compound AON-MG23 of the present invention on the inhibition of cell migration in human breast cancer cells. The degree of cell migration was photographed and analyzed over time after treating the human breast cancer cell line MDA-MB-231 with various concentrations of the compound AON-MG23 of the present invention.

[0043] Figure 5 A schematic diagram of an experiment used to confirm the cell migration inhibition effect of the compound AON-MG23 of the present invention is shown.

[0044] Figure 6 The results show the results of confirming the cell migration inhibitory effect of the compound AON-MG23 of the present invention by pretreating human breast cancer cell line MDA-MB-231-LM3 cells with a single concentration (0.5 μM) of the compound AON-MG23 of the present invention.

[0045] Figure 7 The results show the extent of matrix gel invasion of human breast cancer cell line MDA-MB-231 after being treated with various concentrations of the compound AON-MG23 of the present invention on breast cancer cell metastasis, in order to confirm the inhibitory effect of the compound AON-MG23 of the present invention on breast cancer cell metastasis.

[0046] Figure 8 The results shown are obtained after treating human breast cancer cell line MDA-MB-231-LM3 cells with different concentrations of the compound AON-MG23 of the present invention to confirm its inhibitory effect on cell metastasis in human breast cancer cells.

[0047] Figure 9 Results confirming the effect of the compound AON-MG23 of the present invention on the expression of ANO1 and EGFR proteins in human breast cancer cells are shown.

[0048] Figure 10A and Figure 10B Results confirming the combined effects of the compound AON-MG23 of the present invention and paclitaxel in human breast cancer cells are shown. Figure 10A The human breast cancer cell line SUM149 is shown, and Figure 10B The human breast cancer cell line HCC1806 is shown.

[0049] Detailed Implementation Plan The inventors completed this invention by confirming that the novel compound of this invention inhibits the growth, proliferation, metastasis, tumorigenesis and migration of breast cancer cells, while simultaneously inhibiting ANO1, a calcium-dependent chloride ion channel, and EGFR, an epidermal growth factor receptor. This not only demonstrates excellent anti-cancer effects, but also exhibits high synergistic effects when co-administered with anti-cancer agents.

[0050] The present invention will now be described in detail.

[0051] The present invention provides a pharmaceutical composition for the prevention or treatment of breast cancer, comprising, as an active ingredient, a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof.

[0052] [Chemical Formula 1] The compound represented by Formula 1 can be called “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 in Formula 1, “Ms” represents methanesulfonyl group, i.e. -SO2(CH3).

[0053] Hereinafter, unless otherwise stated, the terms "compound of the present invention" or "compound represented by chemical formula 1" are used as concepts including the compound represented by chemical formula 1 itself, its salts, its isomers, etc.

[0054] In this invention, the term "pharmaceutically acceptable salt" includes all salts derived from pharmaceutically acceptable inorganic acids, organic acids, or bases.

[0055] As used herein, the term "pharmaceutically acceptable" means a compound or composition suitable for contact with the tissues of a subject (e.g., a person) without excessive toxicity, irritation, allergic reactions or other problems or complications, with a reasonable benefit / risk ratio, and within the bounds of reasonable medical judgment.

[0056] 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, p-toluenesulfonic acid, tartaric acid, (+)-L-tartaric acid, di-L-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-acetaminobenzoic acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphorsulfonic acid, decanoic acid, hexanoic acid, caprylic acid, cinnamic acid, cyclohexanesulfonic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid. Galactobionic acid, gentic acid, glucoheponic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, α-oxoglutarate, 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, dicoxalic acid, palmitic acid, palmitic acid, L-pyroglutamic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, tannic acid, thiocyanate, camphorsulfonic acid, and undecanoic acid. Acid addition salts can be prepared by conventional methods, such as 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, acid addition salts can be prepared by heating an equimolar amount of the compound and an acid or alcohol in water and then evaporating the mixture to dryness, or by filtration of the precipitated salt.

[0057] The scope of the compounds of this invention may include not only pharmaceutically acceptable salts, but also all isomers, hydrates and solvates that can be prepared by conventional methods.

[0058] In this invention, the term "isomer" refers to compounds having the same molecular formula but differing in the way their constituent atoms are connected or in their spatial arrangement within the molecule. Isomers include, for example, structural isomers and stereoisomers. Stereoisomers can be diastereomers or enantiomers. Enantiomers are isomers that do not overlap with their mirror images, such as left-handed and right-handed relationships, and are also called optical isomers. Enantiomers are classified as R (Rectus: clockwise) and S (Sinister: counterclockwise) when the four substituents on the chiral central carbon are different from each other. Diastereomers are stereoisomers that are not in a mirror image relationship and can be classified as cis-trans isomers caused by differences in the spatial arrangement of atoms.

[0059] The compounds of this invention are 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 inhibition of breast cancer cell growth, but also the inhibition of breast cancer progression or deterioration caused by migration, invasion, metastasis, tumorigenesis, etc.

[0060] In this invention, "EGFR (epidermal growth factor receptor)" is a transmembrane glycoprotein, a member of the protein kinase superfamily, and a receptor for proteins in the epidermal growth factor family. EGFR is a major regulator of cell growth, and when epidermal growth factor (EGF) binds to EGFR as a ligand, the receptor induces dimerization and tyrosine autophosphorylation, thereby inducing cell proliferation. Overexpression (amplification) or excessive activation of EGFR is frequently observed in various cancers such as anal cancer, breast cancer (especially triple-negative breast cancer), and glioblastoma, and EGFR-associated somatic mutations cause persistent activation of EGFR, thereby inducing uncontrolled cell division. In particular, EGFR gene rearrangement and EGFR gene amplification are patterns observed in various cancers.

[0061] In this invention, "Anoctamin (ANO1)" is a calcium-activated chloride ion channel (Cl... - ANO1, also known as transmembrane protein 16A (TMEM16A), is expressed in various normal cells, including epithelial cells, smooth muscle cells, vascular endothelial cells, and neurons, and performs various physiological functions by regulating humoral secretion, muscle contraction, and nociception. However, ANO1 is also known to be involved in cellular carcinogenesis and cancer development. In fact, overexpression of ANO1 promotes signaling pathways that stimulate proliferation and migration in cancer cells, and inhibition of ANO1 has been reported to suppress 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 has attracted attention as a target for cancer therapy, but no ANO1 inhibitor has yet been found to exhibit excellent anti-cancer effects. The compounds of this invention effectively inhibit ANO1 expression in breast cancer cells and have been shown to inhibit the migration, proliferation, and metastasis of breast cancer cells, thus they can be used for the prevention, treatment, and inhibition of metastasis of breast cancer. Furthermore, previous studies on improving the efficacy of EGFR / HER2 targeted therapy through ANO1 inhibition have shown that the compounds according to the present invention can increase the responsiveness of cancer cells to EGFR / HER targeted therapy through ANO1 inhibition and can inhibit the development of drug resistance.

[0062] In particular, the compounds of the present invention simultaneously inhibit the expression of EGFR and ANO1 in breast cancer cells, thus exhibiting a stronger anti-cancer effect through the simultaneous inhibition of ANO1 and EGFR. The association between ANO1 and EGFR is well-known, and the upregulation of ANO1 is associated with the EGFR signaling pathway and has been reported to have a significant impact 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 co-regulate cell proliferation. Therefore, when the compounds of the present invention are used to simultaneously inhibit EGFR and ANO1, the growth of breast cancer can be inhibited more effectively.

[0063] Meanwhile, it is known that ANO1 is overexpressed in cancer cells and contributes to cancer cell migration and tumor metastasis, and it is also known that EGFR signaling creates a tumor microenvironment conducive to tumor metastasis. Therefore, the compounds according to the invention can effectively inhibit breast cancer metastasis through simultaneous inhibition of ANO1 and EGFR. The term "metastasis" refers to the state in which a malignant tumor has spread from its originating organ to another distant tissue. Therefore, the compositions according to the invention can prevent and treat the systemic spread of breast cancer by inhibiting its metastasis.

[0064] In this invention, "tumor" and "cancer" are used synonymously and refer to a condition typically characterized by uncontrolled cell growth, migration, and proliferation. The cancer according to this invention is breast cancer, including primary and recurrent cancer, and including benign and malignant tumors. In this invention, breast cancer refers to all tumors occurring in the breast, and clinically, breast cancer can be divided into three subgroups based on the presence or absence of major gene expression: 1) estrogen receptor-positive (ER-positive) expressing estrogen receptor (ER), 2) HER2-positive expressing HER2, and 3) triple-negative breast cancer not expressing any of the three genes: estrogen receptor, progesterone receptor (PR), and HER2. Furthermore, breast cancer can be classified as non-invasive or invasive based on whether it invades the basement membrane, and can be classified as ductal carcinoma, lobular carcinoma, etc., based on the breast tissue in which it occurs.

[0065] In this invention, the breast cancer may be one or more selected from the group consisting of ductal carcinoma in situ, 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. Furthermore, according to one embodiment of this invention, the breast cancer may be one or more selected from the group consisting of ductal carcinoma in situ (SUM149 cells, SUM159 cells, and CAL51 cells), inflammatory breast cancer (BCX010 cells and FC-IBC02 cells), triple-negative breast cancer (BT20 cells, MDA-MB-231-LM3 cells, PyMT-N cells, HCC1806 cells, and HCC1937 cells), and metastatic breast cancer (MDA-MB-436 cells), but is not limited thereto.

[0066] "Breast carcinoma in situ" is a non-invasive breast cancer in which cancer cells are confined to the epithelial tissue and do not invade the basement membrane of the ducts, and includes lobular carcinoma in situ and ductal carcinoma in situ.

[0067] Inflammatory breast cancer is one of the deadliest forms of advanced breast cancer, in which cancer cells directly and extensively invade the breast skin to cause symptoms similar to breast inflammation, and it is an invasive form of breast cancer.

[0068] Triple-negative breast cancer (TNBC) is a type of breast cancer that lacks estrogen and progesterone receptors (ER- / PR-) and does not express the HER2 gene (HER2-). It is characterized by resistance to paclitaxel, tamoxifen, and HER2 activity inhibitors (trastuzumab), and is known to overexpress EGFR, a cancer cell growth factor.

[0069] Metastatic breast cancer refers to stage 4 breast cancer where cancer cells have spread to other organs and are difficult to cure completely, with a known 5-year survival rate of only 22%. Treatment decisions must consider the presence or absence of hormone receptor (HR) or human epidermal growth factor receptor 2 (HER-2), the timing of cancer recurrence, the rate of metastasis, and the location of metastases.

[0070] Invasive breast cancer is a cancer that invades the basement membrane of ducts or lobules, and includes invasive ductal carcinoma, invasive lobular carcinoma, mucinous carcinoma, medullary carcinoma, tubular carcinoma, adenoid cystic carcinoma, secretory carcinoma, apocrine gland carcinoma, metaplastic carcinoma, etc.

[0071] Furthermore, the breast cancer according to the present invention can 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 can be associated with one or more mutations selected from the group consisting of EGFR (epidermal growth factor receptor) and ANO1 (calcium-activated chloride channel-1). That is, the cancer according to the present invention can be a breast cancer with mutations in EGFR and / or ANO1. Mutations in EGFR and / or ANO1 include amplification of the EGFR and / or ANO1 gene, overexpression of the protein, excessive activation of the protein, persistent activation of the protein, etc. That is, the breast cancer according to the present invention can have higher expression or activity of EGFR and / or ANO1 than normal cells. Alternatively, the breast cancer according to the present invention can be a breast cancer in which the activated state of EGFR and / or ANO1 is persistent. Since the compound according to the present invention can simultaneously inhibit the expression and activity of ANO1 and EGFR, the compound can exhibit particularly excellent anti-cancer effects against breast cancer with mutations in EGFR and / or ANO1.

[0072] In this invention, the compound or a pharmaceutically acceptable salt thereof may simultaneously inhibit EGFR and ANO1, but is not limited thereto.

[0073] In this invention, the compound or a pharmaceutically acceptable salt thereof may satisfy one or more properties selected from the group consisting of, but is not limited to: (a) Inhibits the proliferation or growth of cancer cells; (b) Inhibits the migration of cancer cells; (c) Inhibits the tumorigenicity of cancer cells; (d) Inhibit cancer metastasis; and (e) Inhibit cancer resistance to anticancer agents.

[0074] In this invention, in (e), the anticancer agent may be a chemoanticancer agent and / or a targeted anticancer agent, but is not limited thereto.

[0075] The inventors have demonstrated through specific embodiments that breast cancer cells treated with the compounds according to the present invention exhibited inhibited growth, proliferation, migration, tumorigenesis, and metastasis (invasiveness).

[0076] In this invention, "tumorigenicity" refers to the ability or tendency to form cancer, and according to one embodiment of the invention, in breast cancer cells (SUM149, BCX010, BT20 and MDA-MB-231-LM3) treated with the compound according to the invention, tumorigenicity was shown to be inhibited in a concentration-dependent manner.

[0077] Furthermore, the inventors have demonstrated that the compounds of the present invention can simultaneously inhibit ANO1 and EGFR (i.e., dual inhibition), and therefore, the compounds of the present invention can exhibit superior anticancer effects compared to single inhibitors of ANO1 or EGFR. In particular, the inhibition of ANO1 can inhibit the development of cancer cell resistance to anticancer agents and enhance the anticancer effect of the anticancer agent. For example, the inventors have experimentally demonstrated that when the compounds of the present invention are co-administered with paclitaxel, a taxane-based chemocancer agent, a high synergistic effect is still observed in breast cancer cells (SUM149 and HCC1806) that are resistant to paclitaxel. Additionally, the inventors have demonstrated that the compounds of the present invention inhibit the growth and tumorigenicity of breast cancer cells SUM149 resistant to paclitaxel (a taxane-based chemocancer agent), olaparib (a PARP inhibitor), and goxatozumab (an antibody targeting TROP-2), as well as paclitaxel-resistant BCX010 and BT20, and doxorubicin-resistant CAL51 breast cancer cells.

[0078] Therefore, in this invention, the pharmaceutical composition can be administered in combination with a chemoanticancer agent or a targeted anticancer agent, and the pharmaceutical composition can be administered simultaneously, separately, or sequentially with the anticancer agent, but is not limited thereto.

[0079] In this invention, the term "chemical anti-cancer agent" refers to agents that primarily act directly on DNA to block DNA replication, transcription, and translation processes or interfere with the synthesis of nucleic acid precursors in metabolic pathways and inhibit cell division, thereby exhibiting anti-cancer activity, i.e., cytotoxicity against cancer cells. In this invention, chemical anti-cancer agents may include paclitaxel and docetaxel as "taxane-based chemical anti-cancer agents," which interfere with the cell division of cancer cells by disrupting the separation of microtubules, organelles involved in cell division and self-replication during cell division, thereby inhibiting proliferation; and actinomycin D, doxorubicin, daunorubicin, mitomycin, and bleomycin as "antibiotic-based chemical anti-cancer agents," which are extracted from Streptomyces, a soil fungus, and are cell cycle non-specific drugs that intercalate between base pairs in DNA to unwind the DNA helix and interfere with DNA and RNA synthesis. That is, in this invention, the chemical anticancer agent may be one or more selected from the group consisting of paclitaxel, docetaxel, actinomycin D, doxorubicin, daunorubicin, mitomycin and bleomycin, but is not limited thereto.

[0080] In this invention, the term "targeted anti-cancer agent" refers to an agent that exhibits anti-cancer effects by targeting proteins or genes specifically altered in cancer cells or cancerous tissues and interfering with molecular activities involved in cancer growth and development. The targeted anti-cancer agent may be one or more selected from the group consisting of EGFR-targeted anti-cancer agents, TROP-2-targeted anti-cancer agents, and PARP-targeted anti-cancer agents. Specifically, the EGFR-targeted anti-cancer agent (EGFR inhibitor) may be cetuximab, osimertinib, gefitinib, afatinib, erlotinib, or lazatinib; the PARP-targeted anti-cancer agent (PARP inhibitor) may be olaparib, niraparib, rucaparib, or tapazolidinib; and the TROP-2-targeted anti-cancer agent may be goxatuzumab, but is not limited thereto, and may include any substance targeting EGFR, PARP, or TROP-2 without limitation.

[0081] Furthermore, the compounds according to the present invention can enhance the anticancer effect of anticancer agents by increasing the activity of anticancer agents against breast cancer or increasing the responsiveness of cancer cells to anticancer agents.

[0082] The enhanced responsiveness of cancer cells to anticancer agents indicates that the inhibitory effects of anticancer agents on cancer cell growth, proliferation, migration, tumorigenesis, and metastasis are further enhanced.

[0083] In this invention, "enhancing an anti-cancer effect" refers to all effects that may thereby strengthen the function of the anti-cancer agent, and includes not only enhancing the anti-cancer effect of the anti-cancer agent (such as inhibiting the growth of cancer cells, inhibiting cancer metastasis and inhibiting cancer recurrence), but also the concept of enhancing the anti-cancer effect by inhibiting the formation of resistance to the anti-cancer agent in cancer cells.

[0084] Therefore, the compounds according to the present invention can be used as compounds co-administered with known anticancer agents to enhance the anticancer effect of the anticancer agents.

[0085] For example, the present invention provides a pharmaceutical composition for the prevention or treatment of breast cancer, comprising as an active ingredient (i) a compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof; and (ii) one or more anticancer agents selected from the group consisting of chemical anticancer agents and targeted anticancer agents.

[0086] In this invention, the compound or a pharmaceutically acceptable salt thereof can inhibit the resistance of cancer cells to the anticancer agent, but is not limited thereto.

[0087] In this invention, the composition may be in the form of a mixture of the compound or a pharmaceutically acceptable salt thereof and the anticancer agent, and may be in the form of simultaneous administration of the compound or a pharmaceutically acceptable salt thereof and the anticancer agent.

[0088] In this invention, the composition can be 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 can be a combination drug composition for simultaneous or sequential administration, comprising a first drug composition containing a pharmaceutically effective amount of the compound or a salt thereof as an active ingredient; and a second drug composition containing a pharmaceutically effective amount of the anticancer agent as an active ingredient. In this case, in the case of sequential administration, the order of administration is not limited, and the administration regimen can be appropriately adjusted according to the patient's condition, etc. That is, when the drug composition is a combination drug composition for sequential administration, the composition can be a composition in which the compound or a salt thereof ("first component") is administered first, followed by the anticancer agent ("second component"), and vice versa.

[0089] Furthermore, since the compounds of the present invention can enhance the anticancer effect of anticancer agents by increasing the activity of anticancer agents against breast cancer or increasing the responsiveness of cancer cells to anticancer agents, the present invention can provide a pharmaceutical composition for enhancing the anticancer effect of anticancer agents against breast cancer, comprising a compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0090] In this invention, the anticancer agent may be one or more selected from the group consisting of chemical anticancer agents and targeted anticancer agents, but is not limited thereto.

[0091] In this invention, the chemical anticancer agent may be one or more selected from the group consisting of paclitaxel, docetaxel, actinomycin D, doxorubicin, daunorubicin, mitomycin, and bleomycin, but is not limited thereto. According to one example of the invention, the chemical anticancer agent may be paclitaxel, but is not limited thereto.

[0092] In this invention, the targeted anticancer agent may be one or more selected from the group consisting of EGFR-targeted anticancer agents, TROP-2-targeted anticancer agents and PARP-targeted anticancer agents, but is not limited thereto.

[0093] In this invention, the pharmaceutical composition can be administered simultaneously, separately, or sequentially with the anticancer agent, and the order of administration is not limited. Furthermore, the administration regimen can be appropriately adjusted according to the type of cancer, the type of anticancer agent, the patient's condition, etc.

[0094] The content of compounds in the compositions of the present invention can be appropriately adjusted according to the symptoms of the disease, the degree of symptom progression, the patient's condition, etc., and can be, for example, from 0.0001 to 99.9 wt% or from 0.001 to 50 wt% based on the total weight of the composition, but is not limited thereto. The content ratio is based on the dry weight after solvent removal.

[0095] The pharmaceutical compositions according to the invention may further include suitable carriers, excipients, and diluents commonly used in the preparation of pharmaceutical compositions. Excipients may be, for example, one or more selected from the group consisting of diluents, binders, disintegrants, lubricants, adsorbents, humectants, film coating materials, and controlled-release additives.

[0096] The pharmaceutical compositions according to the invention can be formulated according to commonly used methods into forms such as powders, granules, sustained-release granules, enteric-coated granules, liquids, eye drops, elixirs, emulsions, suspensions, liniments, lozenges, aromatic waters, lemonade, tablets, sustained-release tablets, enteric-coated tablets, sublingual tablets, hard capsules, soft capsules, sustained-release capsules, enteric-coated capsules, pills, tinctures, soft extracts, dry extracts, fluid extracts, injections, capsules, and infusions, or formulated into topical preparations such as plasters, lotions, pastes, sprays, inhalers, patches, sterile injectable solutions, or aerosols. Topical preparations can be in the form of creams, gels, patches, sprays, ointments, plasters, lotions, liniments, pastes, or wet dressings.

[0097] As carriers, excipients, and diluents that can be included in the pharmaceutical compositions according to the invention, lactose, glucose, sucrose, oligosaccharides, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylparaben, propylparaben, talc, magnesium stearate, and mineral oil may be used.

[0098] For formulation preparation, commonly used diluents or excipients are used, such as fillers, thickeners, binders, wetting agents, disintegrants, and surfactants.

[0099] As an additive for tablets, powders, granules, capsules, pills, and lozenges according to the present invention, the following excipients may be used: corn starch, potato starch, wheat starch, lactose, white sugar, glucose, fructose, D-mannitol, precipitated calcium carbonate, synthetic aluminum silicate, dicalcium phosphate, calcium sulfate, sodium chloride, sodium bicarbonate, purified lanolin, microcrystalline cellulose, dextrin, sodium alginate, methylcellulose, sodium carboxymethyl cellulose, kaolin, urea, colloidal silica, hydroxypropyl starch, hydroxypropyl methylcellulose (HPMC), HPMC1928, HPMC2208, HPMC 2906, HPMC2910, propylene glycol, casein, calcium lactate, and Primojel®; and binders (such as gelatin, gum arabic, ethanol, agar powder, cellulose acetate phthalate, carboxymethyl cellulose, calcium carboxymethyl cellulose, glucose, purified water, sodium caseinate, glycerin, stearic acid, sodium carboxymethyl cellulose, sodium methyl cellulose, methyl cellulose, microcrystalline cellulose, dextrin, hydroxycellulose, hydroxypropyl starch, hydroxymethyl cellulose, purified shellac, starch, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl alcohol, and polyvinylpyrrolidone); and disintegrants ( Such as hydroxypropyl methylcellulose, corn starch, agar powder, methylcellulose, bentonite, hydroxypropyl starch, sodium carboxymethyl cellulose, sodium alginate, calcium carboxymethyl cellulose, calcium citrate, sodium lauryl sulfate, anhydrous silica, 1-hydroxypropyl cellulose, dextran, ion exchange resin, polyvinyl acetate, formaldehyde-treated casein and gelatin, alginic acid, amyl starch, guar gum, sodium bicarbonate, polyvinylpyrrolidone, calcium phosphate, gelling starch, gum arabic, amylopectin, pectin, sodium polyphosphate, ethyl cellulose, white sugar, magnesium aluminum silicate, disorbitol solution and light anhydrous silica); And lubricants (such as calcium stearate, magnesium stearate, stearic acid, hydrogenated vegetable oil, talc, pine sylvestris powder, kaolin, petrolatum, sodium stearate, cocoa butter, sodium salicylate, magnesium salicylate, polyethylene glycol (PEG) 4000, PEG 6000, liquid paraffin, hydrogenated soybean oil (Lubriwax), aluminum stearate, zinc stearate, sodium lauryl sulfate, magnesium oxide, polyethylene glycol, synthetic aluminum silicate, anhydrous silica, higher fatty acids, higher alcohols, silicone oil, paraffin oil, polyethylene glycol fatty acid ethers, starch, sodium chloride, sodium acetate, sodium oleate, dl-leucine and light anhydrous silica).

[0100] As additives to the liquid according to the present invention, water, dilute hydrochloric acid, dilute sulfuric acid, sodium citrate, sucrose monostearate, polyoxyethylene sorbitol fatty acid ester (Tween ester), polyoxyethylene monoalkyl ether, lanolin ether, lanolin ester, acetic acid, hydrochloric acid, ammonia, ammonium carbonate, potassium hydroxide, sodium hydroxide, alcohol-soluble protein, polyvinylpyrrolidone, ethyl cellulose, and sodium carboxymethyl cellulose can be used.

[0101] In the syrup according to the invention, a sugar solution, other sugars or sweeteners may be used, and flavorings, colorings, preservatives, stabilizers, suspending agents, emulsifiers, thickeners, etc. may be used as needed.

[0102] In the emulsion according to the present invention, purified water can be used, and emulsifiers, preservatives, stabilizers, fragrances, etc., can be used as needed.

[0103] In the suspension according to the invention, suspending agents such as gum arabic, tragacanth, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, sodium alginate, hydroxypropyl methylcellulose (HPMC), HPMC1828, HPMC2906, HPMC2910, etc., may be used, and surfactants, preservatives, stabilizers, colorants and fragrances may be used as needed.

[0104] The injectable formulation according to the present invention may include: solvents (such as distilled water for injection, 0.9% sodium chloride solution, Ringer's solution, glucose solution, glucose + sodium chloride solution, PEG, lactated Ringer's solution, ethanol, propylene glycol, non-volatile oils such as sesame oil, cottonseed oil, peanut oil, soybean oil, corn oil, ethyl oleate, isopropyl myristate, and benzyl benzoate); cosolvents (such as sodium benzoate, sodium salicylate, sodium acetate, urea, carbamate, monoethylacetamide, phenylbutazone, propylene glycol, Tween series, nicotinamide, hexamine, and dimethylacetamide); and buffers (such as weak acids and their salts (acetic acid and sodium acetate), weak bases and their salts (ammonia and acetylene). Ammonium chloride, organic compounds, proteins, albumin, peptone, and gums; isotonic agents, such as sodium chloride; stabilizers (such as sodium bisulfite (NaHSO3), carbon dioxide gas, sodium metabisulfite (Na2S2O5), sodium sulfite (Na2SO3), nitrogen (N2), and ethylenediaminetetraacetic acid); sulfating agents (such as 0.1% sodium bisulfite, sodium formaldehyde sulfoxylate, thiourea, disodium ethylenediaminetetraacetate, and sodium acetone bisulfite); analgesics (such as benzyl alcohol, chlorobutanol, procaine hydrochloride, glucose, and calcium gluconate); and suspending agents (such as sodium carboxymethyl cellulose, sodium alginate, Tween 80, and aluminum monostearate).

[0105] In the suppositories according to the invention, a matrix may be used, such as cocoa butter, lanolin, Witopsol, polyethylene glycol, glycerin gelatin, methylcellulose, carboxymethylcellulose, a mixture of stearic acid and oleic acid, subanal, cottonseed oil, peanut oil, palm oil, cocoa butter + cholesterol, lecithin, cetearyl alcohol, glyceryl monostearate, Tween or Span, imhausen, monolan (propylene monostearate), glycerin, Adeps solidus, buytyrum Tego-G, cebes Pharma16, hexalide base95, cotomar, Hydrokote SP, S-70-XXA, S-70-XX75 (S-70-XX95), Hydrokote25, Hydrokote711, idropostal, massa estrarium (A,AS,B,C,D,E,I,T), masa-MF, masupol, masupol-15, neosuppostal-N, paramount-B, supposiro OSI, OSIX, A, B, C, D, H, L, suppository matrix type IV AB, B, A, BC, BBG, E, BGF, C, D, 299, suppository N, Es, Wecoby W, R, S, M, Fs, and tegester triglyceride substances (TG-95, MA, 57).

[0106] Solid dosage forms for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid dosage forms are formulated by mixing a composition with at least one excipient, such as starch, calcium carbonate, sucrose, lactose, gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used.

[0107] Examples of liquid formulations for oral administration include suspensions, oral solutions, emulsions, syrups, etc., and these liquid formulations may include various types of excipients other than simple, commonly used diluents such as water and liquid paraffin, such as wetting agents, sweeteners, flavorings, preservatives, etc. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized formulations, and suppositories. Non-limiting examples of non-aqueous solvents and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.

[0108] The pharmaceutical compositions according to the invention are administered in a pharmaceutically effective amount. In this invention, "the pharmaceutically effective amount" means an amount sufficient to treat a disease in a reasonable benefit / risk ratio applicable to medicine, and the effective dose level can be determined based on factors including the patient's disease type, disease severity, drug activity, drug sensitivity, timing of administration, route of administration, excretion rate, treatment duration, and concurrently used drugs, as well as factors well known in other medical fields.

[0109] The compositions according to the invention can be administered as a single therapeutic agent or in combination with other therapeutic agents, can be administered sequentially or simultaneously with therapeutic agents in the related art, and can be administered in single or multiple doses. It is important to administer the composition in the minimum amount necessary to achieve maximum effect without any side effects, taking all the foregoing factors into account, and this can be readily determined by those skilled in the art.

[0110] The pharmaceutical compositions of the present invention can be administered to subjects via various routes. All methods of administration are foreseeable, and the pharmaceutical compositions can be administered, for example, by oral administration, subcutaneous injection, intraperitoneal injection, intravenous injection, intramuscular injection, intrathecal (perispinal space) injection, sublingual administration, administration via buccal mucosa, rectal insertion, vaginal insertion, ocular administration, intraauricular administration, intranasal administration, inhalation, oral or nasal spray, transdermal administration, percutaneous administration, etc.

[0111] The determination of the pharmaceutical composition of the present invention depends on the type of drug as the active ingredient, and 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 amount of the composition according to the present invention can vary depending on the patient's age, sex, and weight, and generally, it can be administered daily or every other day at a dose of 0.001 to 150 mg per kg of body weight, preferably 0.01 to 100 mg, or once to three times daily. However, the dosage can be increased or decreased depending on the route of administration, the severity of the disease, sex, weight, age, etc., and therefore, the above dosage does not limit the scope of the present invention in any way.

[0112] As used in this article, “subject” means a person who needs treatment for a disease, and more specifically, it means a mammal, such as a human or non-human primate, mouse, rat, dog, cat, horse and cow.

[0113] As used herein, “administration” means providing a subject with a predetermined composition of the invention by any suitable method. As used herein, the term “prevention” means all actions that inhibit or delay the onset of a target disease. As used herein, the term “treatment” means all actions that alleviate or beneficially alter a target disease and its associated abnormal metabolic symptoms by administering a pharmaceutical composition according to the invention. As used herein, the term “alleviation” means all actions that reduce the degree of parameters (e.g., symptoms) associated with a target disease by administering a composition according to the invention.

[0114] In addition, the present invention provides a kit for the prevention or treatment of breast cancer, comprising a pharmaceutical composition according to the present invention and instructions for use.

[0115] In addition to compounds and anticancer agents, the kit according to the present invention may further contain other components, compositions, solutions, devices, etc., commonly used for the prevention or treatment of breast cancer, but is not limited thereto. In particular, it may contain instructions on the proper use and storage of the compounds according to the present invention. All components contained in the kit may be used once or multiple times, with no limit on the number of uses or the order in which the various materials are used; the application of the various materials may be performed simultaneously or at different times.

[0116] In addition to the compounds and anticancer agents, the kit of the present invention may further include a container. The container can be used for packaging configurations, as well as for storage and protection configurations. The container material may be, for example, bottles, boxes, bags, envelopes, tubes, ampoules, etc., which may be partially or wholly made of plastic, glass, paper, foil, wax, etc. The container may be equipped with a fully or partially removable closure device, which is originally part of the container or can be attached to the container mechanically, adhesively, or otherwise, and may also be equipped with a stopper that allows contact with the contents through a hypodermic needle. The kit may include an outer packaging, which may contain instructions on the use of the components, but is not limited thereto.

[0117] In this specification, "active ingredient" refers to a component that exhibits the intended activity on its own or that can exhibit the intended activity together with an inactive carrier or the like.

[0118] The terms or vocabulary used in this specification and claims should not be construed as limited to their ordinary or dictionary meanings, but should be interpreted as meanings and concepts consistent with the technical concept of the invention, based on the principle that the inventor may appropriately define terms and concepts in order to best describe the inventor's own invention.

[0119] [Inventive Method] The following preferred embodiments are presented to aid in understanding the present invention. However, these embodiments are provided merely to facilitate a clearer understanding of the invention, and the scope of the invention is not limited to these embodiments.

[0120] [Example] Example 1. Synthesis of compound AON-MG23 of the present invention <Step 1> Synthesis of N-cyclopropyl-N-(2-nitrophenyl)methanesulfonamide [Reaction Scheme 1] 1-Fluoro-2-nitrobenzene (1.00 eq.) and cyclopropylamine (1.00 eq.) were dissolved in acetonitrile (ACN), and methanesulfonyl chloride (MsCl, 1.0 eq.) was slowly added at 0 °C, while the resulting solution was stirred at the same temperature for one hour. Subsequently, cesium carbonate (Cs₂CO₃, 5.00 eq.) was added at the same temperature, and the resulting mixture was stirred under reflux overnight. After the reaction was complete, the temperature was lowered to room temperature, and extraction was performed using ethyl acetate and water. Anhydrous sodium sulfate was added to the organic layer and stirred. The resulting 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-nitrophenyl)methanesulfonamide as a pale yellow solid in 36% yield.

[0121] <Step 2> Synthesis of N-(2-aminophenyl)-N-cyclopropylmethanesulfonamide [Reaction Scheme 2] The N-cyclopropyl-N-(2-nitrophenyl)methanesulfonamide (1.00 eq.) synthesized in step 1 was added to 1,4-dioxane and water (3:1), and the mixture was stirred. The reactor was then cooled to 0°C, and zinc (Zn, 10.0 eq.) and ammonium chloride (NH4Cl, 10.0 eq.) were added. The temperature was then gradually increased over four hours with stirring. After the reaction was complete, the mixture was filtered through diatomaceous earth, and the filtrate was extracted with ethyl acetate and water. Anhydrous sodium sulfate was added to the organic layer and stirred. The resulting mixture was filtered through a filter, and the filtrate was concentrated under reduced pressure. The concentrated residue was used in step 3 without a separate purification process.

[0122] <Step 3> Synthesis of N-cyclopropyl-N-(2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)methanesulfonamide [Reaction Scheme 3] The N-(2-aminophenyl)-N-cyclopropylmethanesulfonamide (1.00 eq.) synthesized in step 2 was added to isopropanol (IPA), and 2,4,5-trichloropyrimidine (1.1 eq.) and N,N-diisopropylethylamine (DIPEA, 2.5 eq.) were added at room temperature. The resulting mixture was then stirred under reflux overnight. After the reaction was complete, the mixture was evaporated under reduced pressure and extracted with water and dichloromethane. The organic layer was washed with 2N hydrochloric acid (HCl), and anhydrous sodium sulfate was added to the organic layer, followed by stirring. The mixture was then 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-dichloropyrimidine-4-yl)amino)phenyl)methanesulfonamide as a pale yellow solid in 58.9% yield.

[0123] <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 [Reaction Scheme 4] The N-cyclopropyl-N-(2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)methanesulfonamide (1.00 eq.) synthesized in step 3 was added to ethanol (EtOH), followed by the addition of 1-(4-amino-3-methoxyphenyl)-N,N-dimethylpiperidin-4-amine (1.00 eq.) and trifluoroacetic acid (TFA, 1.95 eq.) at room temperature. The resulting mixture was stirred overnight under reflux. After the reaction was complete, the mixture was neutralized with 1N sodium hydroxide (NaOH) solution and extracted with water and ethyl acetate. Anhydrous sodium sulfate was added to the organic layer, the resulting mixture was mixed and 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 (AON-MG23) as a yellow solid in 25% yield.

[0124] 1H nuclear magnetic resonance (NMR) (500MHz, dimethyl sulfoxide (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, 1.6Hz, 1H), 7.35 (d, J=8.7Hz, 1H), 7.22 (d, J=8.1Hz, 1H), 7.15 (td, J=7.6, 1.6Hz, 1H), 6.63 (d, J=2.5Hz, 1H), 6.48 (d d, J=8.7, 2.5Hz, 1H), 3.75(s, 3H), 3.72(d, J=12.2Hz, 2H), 3.23(m, 4H), 2.68(td, J=12.1, 2.5Hz, 2H), 2.22(s, 6H), 1.86(d, J=12.4Hz, 2H), 1.51(qd, J=12.0, 3.9Hz, 2H), 1.04–0.92(m, 2H), 0.55–0.49(m, 1H), 0.17–0.14(m, 1H). High-resolution mass spectrometry (HRMS): 585.2294, calculated value: 585.2289.

[0125] Example 2. Confirmation of the inhibitory effect of the compound AON-MG23 of the present invention on the proliferation of breast cancer cells. Human breast cancer cell line MDA-MB-231 cells were used at a rate of 1x10 5 Cells were seeded at a density of 100 cells / well in 96-well plates and cultured for 24 hours. Subsequently, cells were treated with various concentrations of the compound AON-MG23 of the present invention and cultured for 48 hours. Cells were treated with various concentrations of the compound of the present invention at 0 μM, 0.1 μM, 0.25 μM, 0.5 μM, 1 μM, 2 μM, 4 μM, 8 μM, and 16 μM. 105 μL of a cell counting kit (CCK) reagent was added and allowed to react for one hour, after which absorbance was measured at 450 nm.

[0126] As a result, Figure 1 As shown, the compound AON-MG23 of the present invention has been shown to inhibit the proliferation of breast cancer cells.

[0127] Example 3. Confirmation of the inhibitory effect of the compound AON-MG23 of the present invention on the proliferation of breast cancer cells. To confirm the inhibitory effect of the compounds of the present invention on the proliferation of breast cancer cells, a colony formation test was performed. Specifically, six breast cancer cell lines (SUM149, BCX010, BT20, MDA-MB-231-LM3, CAL51, and PyMT-N) were seeded in 6-well cell culture plates at a density of 250 or 1,000 cells per well. On the second day, the cell culture medium was removed and replaced with cell culture medium containing 0 μM, 0.25 μM, 0.5 μM, and 1 μM of the compound AON-MG23 of the present invention. After culturing the cells for 11 to 14 days, the resulting cell colonies were stained and photographed, and then the cell colonies were counted and analyzed using ImageJ software.

[0128] As a result, Figures 2A to 2C As shown, treatment with the compound AON-MG23 of the present invention confirmed that cell colony formation in all six breast cancer cell lines was inhibited.

[0129] Example 4. Confirmation of the tumorigenic inhibitory effect of the compound AON-MG23 of the present invention on breast cancer cells. To confirm the tumorigenic inhibitory effect of the compounds of the present invention on breast cancer cells, an anchorage-independent soft agar assay was performed. Specifically, 0.5% or 0.7% agar was added to cell culture medium diluted with the compounds of the present invention at concentrations of 0 nM, 100 nM, 500 nM, and 1000 nM. 2 ml of 0.5% agar containing the various concentrations of the compounds of the present invention was added to a 6-well cell culture plate and cured at room temperature. Subsequently, 1 ml of 1x10⁻⁶ agar was added to the plate. 4 Four breast cancer cell lines (SUM149, BCX010, BT20, and MDA-MB-231-LM3) were mixed in a 1:1 ratio with 1 ml of 0.7% agar containing various concentrations of the compounds of the present invention to prepare a 0.35% solution, and 2 ml of this solution was placed on top of solidified 0.5% agar. The mixture was then solidified at room temperature until the upper layer was fixed, and the cells were cultured for two weeks in an incubator at 37°C and 5% CO2. The resulting cell clones were stained and photographed, and then the cell clones were counted and analyzed using ImageJ software.

[0130] As a result, Figure 3A and 3B As shown, tumorigenicity of four breast cancer cell lines was inhibited starting with 100 nM of the compound AON-MG23 of the present invention.

[0131] Example 5. Confirmation of the inhibitory effect of the compound AON-MG23 of the present invention on cell migration in breast cancer cells. Human breast cancer cell line MDA-MB-231 cells were used at a rate of 7 x 104 Cells were seeded at a density of cells / well in SPLScarBlock plates (SPLLIFE SCIENCES) and cultured for 24 hours. After 20 hours, the barrier blocks were removed, and at the same time, the compound AON-MG23 of the present invention was administered at various concentrations. Subsequently, the cells were cultured in a CO2 incubator at 37°C for 24 hours. Cells were treated with various concentrations of the compound of the present invention at 0 μM, 0.5 μM, 1 μM, 2 μM, and 4 μM. Photographs were taken before and after each culture, and cell migration distance was measured using ImageJ software. Based on these results, inhibition of cell migration was analyzed.

[0132] As a result, Figure 4 As shown, when cells were treated with the compound of the present invention at a concentration of 0.5 μM, the migration of MDA-MB-231 cells was inhibited by 50% compared with the control group.

[0133] Example 6. Confirmation of the inhibitory effect of the compound AON-MG23 of the present invention on cell migration in breast cancer cells. The breast cancer cell line MDA-MB-231-LM3 was prepared by pretreatment with 0.5 μM of the compound AON-MG23 of the present invention, and untreated cells were also prepared. Figure 5 As shown, the 6x10 groups of untreated and pretreated groups are... 4 Cells were seeded on top of a membrane filter (Transwell membrane insert, Corning) in cell culture medium without 5% fetal bovine serum (FBS). The cell-seeded membrane filter was placed in a 24-well plate of cell culture medium supplemented with FBS and incubated at 37°C and 5% CO2 for eight hours. Cells that migrated to the bottom of the membrane filter were stained, photographed under a microscope, and counted and analyzed using ImageJ software.

[0134] As a result, Figure 6 As shown, cell migration was inhibited in the group pretreated with the compound AON-MG23 of the present invention compared with the untreated group.

[0135] Example 7. Confirmation of the inhibitory effect of the compound AON-MG23 of the present invention on breast cancer cell metastasis. Human breast cancer cell line MDA-MB-231 cells were used at a rate of 6 x 10 4Cells were seeded at a density of 10 cells / well on top of a matrix gel-coated filter (Transwell invasion chamber, Corning), treated with the compound AON-MG23 of this invention (0, 0.5, 1, 2, 4 μM), and cultured in a CO2 incubator at 37°C for 20 hours. After culture, cells were fixed and stained using a Diff-Quick staining kit (Sysmex, Kobe, Japan). The stained cells were imaged under a microscope, and cell counting and statistical analysis were performed using ImageJ software.

[0136] As a result, Figure 7 As shown, the group treated with the compound AON-MG23 of the present invention exhibited a reduced degree of penetration into the matrix gel compared with the untreated control group, thereby inhibiting the metastatic potential of cancer cells.

[0137] Example 8. Confirmation of the inhibitory effect of the compound AON-MG23 of the present invention on breast cancer cell metastasis. The breast cancer cell line MDA-MB-231 was used at 6x10 4 Cells were seeded at a density of 10 cells / well on top of a matrix gel-coated membrane filter (Transwell membrane insert, Corning). Subsequently, the cells were treated with the compound AON-MG23 of this invention at concentrations of 0 μM (DMSO), 0.5 μM, and 1 μM, and cultured in a CO2 incubator at 37°C for 24 hours. After 24 hours of culture, the cells on the bottom surface of the membrane filter were stained, photographed under a microscope, and counted and analyzed using ImageJ software.

[0138] As a result, Figure 8 As shown, the experimental group treated with the compound AON-MG23 of the present invention exhibited a reduced degree of penetration into the matrix gel compared with the untreated control group, and the reduction in matrix gel penetration was dependent on the AON-MG23 treatment concentration.

[0139] Example 9. Confirmation of the effect of the compound AON-MG23 of the present invention on the expression of calcium-activated chloride channel-1 (ANO1) and epidermal growth factor receptor (EGFR) proteins in human breast cancer cell lines. The human breast cancer cell line MDA-MB-231 was used at a dose of 5 × 10⁻⁶. 5Cells were seeded at a density of 10 cells / dish in 60 mm culture dishes and cultured for 24 hours. Subsequently, cells were treated with the compound AON-MG23 of the present invention at concentrations of 0.125 μM, 0.25 μM, 0.5 μM, 1 μM, and 2 μM, while an untreated control group was treated with DMSO and cultured for 48 hours. After culture, cells were recovered and lysed for Western blotting. Antibodies used for Western blotting included anti-ANO1 antibody (Abcam, ab53212), anti-EGFR antibody (Cell Signaling, #4267S), and anti-glyceraldehyde-3-phosphate dehydrogenase (GAPDH) antibody (Cell Signaling, #5174), and protein concentrations were quantified using bovine serum albumin (BSA) assay (protein quantification, BSA assay) (Pierce, Cat. 23225). After cell lysis, proteins were separated by molecular weight using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) in equal amounts (20 μg). After transferring the proteins to a polyvinylidene fluoride (PVDF) membrane (Bio-Rad), the membrane was treated with 5% blocking buffer (5% skim milk in Tris-buffered saline containing 0.1% Tween 20) for one hour at room temperature. The membrane was then treated with primary antibody and incubated at 4°C for 18 hours. After the reaction, the membrane was washed three times with TBS-T for 10 minutes each at room temperature. Subsequently, the membrane was treated with a secondary antibody labeled with horseradish peroxidase for one hour at room temperature, followed by three washes with TBS-T for 10 minutes each. After washing, the membrane was treated with an enhanced chemiluminescence (ECL) kit (Thermo, West Pico Plus) to induce the reaction, and the results were visualized using a DaVinci-Q instrument (Youngin Labplus CO.,LTD.). The visualization results were analyzed by quantifying the amount of each protein using ImageJ software.

[0140] As a result, Figure 9 As shown, the compound AON-MG23 of the present invention reduced both ANO1 and EGFR proteins in breast cancer cell lines, with the reduction starting from the 1 μM treatment group for EGFR protein and from the 0.5 μM treatment group for ANO1 protein.

[0141] Example 10. Confirmation of the drug combination effect of the compound AON-MG23 of the present invention on human breast cancer cells. Based on the results of the sulforhodamine B assay (SRB assay), the combination effect of the compound AON-MG23 of the present invention was confirmed using the Bliss score. Specifically, human breast cancer cell lines SUM149 and HCC1806 were used at a ratio of 1x10⁻⁶.3 Cells were seeded at a density of 100 cells / well in 96-well cell culture plates. On the second day, paclitaxel, the drug to be tested for its combination effect with the compound AON-MG23 of the present invention, was diluted to the concentration used for testing, and the cells were cultured for 24 hours. After carefully removing the cell culture medium, the cells were co-treated with different concentrations of AON-MG23 and paclitaxel and cultured for five days. After five days of co-treatment, the culture medium mixed with the drugs was removed, and 10% trichloroacetic acid (TCA) was added to each well for fixation at 4°C for one hour. After removing the TCA, the 96-well plates were washed five times with tap water and dried at room temperature for one hour. Subsequently, 0.4% SRB solution (sulforhodamine B in 1% acetic acid) was added to each well to stain the cells for 30 minutes at room temperature. After removing the 0.4% SRB solution, the plates were washed five times with 1% acetic acid and dried again for one hour. After drying, 200 μL of 10 mM Tris-base (pH 10.5) was added to each well, and the dye for staining cells was dissolved by stirring at room temperature for 10 minutes. The absorbance of the dissolved solution was measured at 540 nM using a plate reader. The measured absorbance values ​​were compared with the control group, converted to percentages, and saved in Excel format. Subsequently, the Excel file including percentage data was uploaded to https: / / synergyfinder.fimm.fi / to analyze the extent of synergistic effects during combined drug treatment. The presence of synergistic effects was assessed based on the following criteria according to the relevant literature (Bliss, CI (1939). The toxicity of poisons applied jointly. Annals of Applied Biology, 26(3), 585-615.): score > 0 indicates synergistic effect; score = 0 indicates independent effect; and score < 0 indicates antagonistic effect.

[0142] like Figure 10A and 10B As shown, the Bliss synergistic scores of the compounds AON-MG23 and paclitaxel in the human breast cancer cell lines SUM149 and HCC1806 confirm that a high synergistic effect of 18.743 was observed in the SUM149 cell line and a high synergistic effect of 9.249 was observed in the HCC1806 cell line.

[0143] The above description of the present invention is intended for illustrative purposes, and those skilled in the art will understand that various modifications can be made to it in other specific forms without departing from the technical spirit or essential characteristics of the invention. Therefore, the above embodiments should be understood in all respects as illustrative and not restrictive.

[0144] [Industrial Applicability] The novel compound of this invention not only significantly inhibits the growth, proliferation, migration, tumorigenesis, and metastasis of breast cancer cells, but also simultaneously inhibits ANO1 and EGFR in breast cancer cells, thereby exhibiting a stronger anti-cancer effect through the dual inhibition of these two proteins. Furthermore, when used in combination with anticancer agents, this compound can further enhance the efficacy of the anticancer agents and inhibit cancer drug resistance. Therefore, this compound can be used on its own as a dual-target anticancer agent against ANO1 and EGFR, and can also be used as a combination formulation with anticancer agents. Therefore, it is expected to be utilized in various ways in the prevention and treatment of breast cancer, and thus has industrial applicability.

Claims

1. A pharmaceutical composition for the prevention or treatment of breast cancer, comprising, as an active ingredient, a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] 。 2. The pharmaceutical composition according to claim 1, wherein the compound or a pharmaceutically acceptable salt thereof simultaneously inhibits epidermal growth factor receptor (EGFR) and anoctamin-1 (ANO1).

3. The pharmaceutical composition according to claim 1, wherein the compound or a pharmaceutically acceptable salt thereof satisfies one or more properties selected from the group consisting of: (a) Inhibits the proliferation or growth of cancer cells; (b) Inhibits the migration of cancer cells; (c) Inhibits the tumorigenicity of cancer cells; (d) Inhibit cancer metastasis; and (e) Inhibit cancer resistance to anticancer agents.

4. The pharmaceutical composition according to claim 3, wherein the anticancer agent is a chemoanticancer agent or a targeted anticancer agent.

5. The pharmaceutical composition according to claim 4, wherein the chemical anticancer agent is one or more selected from the group consisting of paclitaxel, docetaxel, actinomycin D, doxorubicin, daunorubicin, mitomycin and bleomycin.

6. The pharmaceutical composition according to claim 4, wherein the targeted anticancer agent is one or more selected from the group consisting of EGFR-targeted anticancer agents, trophoblast surface antigen 2 (TROP-2)-targeted anticancer agents, and poly(ADP-ribose) polymerase (PARP)-targeted anticancer agents.

7. The pharmaceutical composition according to claim 1, wherein the breast cancer is selected from one or more of the group consisting of ductal carcinoma in situ, 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. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is administered in combination with a chemoanticancer agent or a targeted anticancer agent.

9. The pharmaceutical composition according to claim 8, wherein the pharmaceutical composition is administered simultaneously, separately, or sequentially with the anticancer agent.

10. A pharmaceutical composition for the prevention or treatment of breast cancer, comprising, as an active ingredient: (i) a compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof; and (ii) Select one or more anticancer agents from the group consisting of free chemical anticancer agents and targeted anticancer agents: [Chemical Formula 1] 。 11. The pharmaceutical composition of claim 10, wherein the compound or a pharmaceutically acceptable salt thereof inhibits the resistance of cancer cells to the anticancer agent.

12. The pharmaceutical composition of claim 10, wherein the composition is in the form of a mixture of the compound or a pharmaceutically acceptable salt thereof and the anticancer agent.

13. The pharmaceutical composition of claim 10, wherein the composition comprises the compound or a pharmaceutically acceptable salt thereof and the anticancer agent respectively formulated for simultaneous, separate or sequential administration.

14. A pharmaceutical composition for enhancing the anticancer effect of an anticancer agent against breast cancer, comprising, as an active ingredient, a compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] 。 15. The pharmaceutical composition of claim 14, wherein the anticancer agent is one or more selected from the group consisting of chemoanticancer agents and targeted anticancer agents.

16. The pharmaceutical composition according to claim 15, wherein the chemical anticancer agent is one or more selected from the group consisting of paclitaxel, docetaxel, actinomycin D, doxorubicin, daunorubicin, mitomycin and bleomycin.

17. The pharmaceutical composition of claim 15, wherein the targeted anticancer agent is one or more selected from the group consisting of EGFR-targeted anticancer agents, trophoblast surface antigen 2 (TROP-2)-targeted anticancer agents, and poly(ADP-ribose) polymerase (PARP)-targeted anticancer agents.

18. The pharmaceutical composition according to claim 14, wherein the pharmaceutical composition is administered simultaneously, separately, or sequentially with the anticancer agent.

19. A method for preventing, improving, or treating breast cancer, comprising administering, in a pharmaceutically effective amount, a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof to a subject in need; or the step of comprising a composition containing the compound or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] 。 20. The use of a compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof; or a composition comprising such compound or a pharmaceutically acceptable salt thereof for the prevention, improvement or treatment of breast cancer: [Chemical Formula 1] 。 21. Use of a compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof; or a composition comprising the compound or a pharmaceutically acceptable salt thereof, in the preparation of an agent for the prevention, improvement, or treatment of breast cancer: [Chemical Formula 1] 。 22. A method for enhancing the anticancer effect of an anticancer agent against breast cancer, comprising administering, to a subject in need, in a pharmaceutically effective amount, a compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof; or a composition comprising the compound or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] 。 23. Use of a compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof; or a composition comprising the compound or a pharmaceutically acceptable salt thereof, for enhancing the anticancer effect of an anticancer agent against breast cancer: [Chemical Formula 1] 。 24. Use of a compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof; or a composition comprising the compound or a pharmaceutically acceptable salt thereof, in the preparation of an formulation for enhancing the anticancer effect of an anticancer agent against breast cancer: [Chemical Formula 1] 。 25. A method for preventing, improving, or treating breast cancer, comprising administering, in a pharmaceutically effective amount, to a subject in need of (i) a compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof; and (ii) one or more anticancer agents selected from the group consisting of chemoanticancer agents and targeted anticancer agents; or a composition comprising the compound or a pharmaceutically acceptable salt thereof and said one or more anticancer agents: [Chemical Formula 1] 。 26. (i) a compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof; and (ii) one or more anticancer agents selected from the group consisting of chemical anticancer agents and targeted anticancer agents; or the use of a composition comprising the compound or a pharmaceutically acceptable salt thereof and one or more of the anticancer agents for the prevention, improvement or treatment of breast cancer: [Chemical Formula 1] 。 27. (i) a compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof; and (ii) one or more anticancer agents selected from the group consisting of chemical anticancer agents and targeted anticancer agents; or the use of a composition comprising the compound or a pharmaceutically acceptable salt thereof and one or more of the anticancer agents for the preparation of an agent for the prevention, improvement or treatment of breast cancer: [Chemical Formula 1] 。

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