KR102571432B1 - Composition for treating cancer containing indazolyl ester and amide derivative - Google Patents

Abstract

The present invention relates to a composition for preventing or treating cancer, including as an active ingredient an indazolyl ester and amide derivative exhibiting high reactivity to cancer, particularly lung cancer.
Cancer is one of the most common causes of death worldwide. Among these cancers, lung cancer remains the world's most lethal malignant tumor. Despite improvements in surgical treatment, systemic treatment, and radiation therapy, the 5-year survival rate for all patients diagnosed with lung cancer is on the order of 15 to 20%.
Since the compound provided in the present invention exhibits high reactivity to intractable lung cancer, it is expected to be actively used in the medical and health fields.

Description

Composition for treating cancer containing indazolyl ester and amide derivative {Composition for treating cancer containing indazolyl ester and amide derivative}

The present invention relates to a composition for preventing or treating cancer comprising an indazolyl ester and an amide derivative as an active ingredient.

Cancer is one of the most common causes of death worldwide. Approximately 10 million new cases occur each year, accounting for approximately 12% of all deaths, making it the third leading cause of death.

Among these cancers, lung cancer remains the world's most lethal malignant tumor. Despite improvements in surgical treatment, systemic treatment, and radiation therapy, the 5-year survival rate for all patients diagnosed with lung cancer is on the order of 15 to 20%. Lung cancer includes two main types: Small Cell Lung Cancer (SCLC) and Non-Small Cell Lung Cancer (NSCLC). SCLC accounts for 15-18% of all lung cancers, and NSCLC accounts for about 80%-85%. Other lung cancer types other than SCLC and NSCLC, such as adenoid cystic carcinoma, lymphoma and sarcoma, are rare. SCLC and NSCLC are treated differently. SCLC grows rapidly and is highly metastatic, but is more responsive to chemotherapy and radiation therapy than other cell types of lung cancer, and thus has a good prognosis. In the case of NSCLC, a cure can be expected if it is detected early and surgical treatment is performed. However, NSCLC that has progressed to some extent due to failure in early diagnosis has a problem that is difficult to treat because of low drug response.

Therefore, the present invention has been made to solve the above problems, and relates to a pharmaceutical composition containing indazolyl ester and amide derivatives exhibiting high reactivity to cancer, particularly lung cancer, as active ingredients.

One object of the present invention is to provide a composition capable of preventing, improving or treating cancer, including indazolyl ester and amide derivatives.

Another object of the present invention is to provide a method for preventing, improving or treating cancer using the above compounds.

However, the technical problem to be achieved by the present invention is not limited to the above-mentioned problems, and other problems not mentioned will be clearly understood by those skilled in the art from the following description.

Hereinafter, various embodiments described herein are described with reference to the drawings. In the following description, numerous specific details are set forth, such as specific forms, compositions and processes, etc., in order to provide a thorough understanding of the present invention. However, certain embodiments may be practiced without one or more of these specific details, or with other known methods and forms. In other instances, well known processes and manufacturing techniques have not been described in specific detail in order not to unnecessarily obscure the present invention. Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, form, composition or characteristic described in connection with the embodiment is included in one or more embodiments of the invention. Thus, the appearances of "in one embodiment" or "an embodiment" in various places throughout this specification do not necessarily refer to the same embodiment of the invention. Additionally, particular features, forms, compositions, or properties may be combined in one or more embodiments in any suitable way.

Unless otherwise defined in the specification, all scientific and technical terms used herein have the same meaning as commonly understood by a person skilled in the art to which the present invention belongs.

In the present invention, "cancer" is characterized by uncontrolled cell growth, and due to such abnormal cell growth, a cell mass called a tumor is formed, penetrates into surrounding tissues, and in severe cases, metastasizes to other organs of the body. means that Scientifically, it is also called neoplasia. Cancer is an intractable chronic disease that in many cases cannot be fundamentally cured even if treated with surgery, radiation, and chemotherapy, causing pain to patients and ultimately leading to death. There are many causes of cancer, but internal factors and external factors. Although it has not been precisely clarified how normal cells are transformed into cancer cells through any mechanism, it is known that a significant number of cancers are affected by external factors such as environmental factors. Internal factors include genetic factors and immunological factors, and external factors include chemicals, radiation, and viruses. Genes involved in the development of cancer include oncogenes and tumor suppressor genes, and cancer occurs when the balance between these genes is disrupted by the internal or external factors described above. The cancer includes breast cancer, uterine cancer, esophageal cancer, stomach cancer, brain cancer, rectal cancer, colon cancer, lung cancer, skin cancer, ovarian cancer, cervical cancer, kidney cancer, blood cancer, pancreatic cancer, prostate cancer, testicular cancer, laryngeal cancer, oral cancer, head and neck cancer, thyroid cancer, It may be liver cancer, bladder cancer, osteosarcoma, lymphoma, leukemia, etc., and if the progression of cancer, such as differentiation and / or proliferation of the tumor treated in the present invention, is dependent on the cancer cells and / or cancer stem cells described in the present invention, this Although not limited, it may be lung cancer, preferably non-small cell lung cancer, more preferably non-small cell lung cancer, more preferably NRF2 protein, or non-small cell lung cancer in which the gene encoding it is overexpressed compared to normal. At this time, the cancer stem cell (CSC) refers to cancer cells in a comprehensive sense that have self-renewal ability or differentiation ability, which is a unique ability of stem cells, and cancer stem cells in cancer tissues account for 0.1 to 5%. It is presumed to exist between The cancer stem cells are under normal tumor growth conditions (the "normal tumor growth conditions" refer to a state in which there is no cell stress due to sufficient nutrients (glucose) necessary for cell growth and sufficient growth conditions in the tumor microenvironment). Unlike normal cancer cells, it has a characteristic of slow proliferation. In addition, it may have resistance to anticancer drugs by maintaining a dormant state, and unlike normal tumor cells, the expression of transcriptional regulators such as PGC-1α is controlled, so that the function of major metabolic regulators is higher than that of normal cancer cells. There are different characteristics. It comprehensively refers to cells with invasion and/or metastatic ability by acquiring resistance to cell death (apoptosis) in a nutrient deprivation state through the regulation of these different metabolisms and the cell signaling system associated therewith. However, it is not limited thereto as long as it is a cell capable of differentiating into a general cancer cell.

In the present invention, as a result of screening various candidate substances, a compound represented by the following formula A was derived as an anti-cancer candidate substance, and 4 kinds (formulas 1 to 4) expected to be effective among its derivatives were selected.

[Formula A]

[Formula 1]

[Formula 2]

[Formula 3]

[Formula 4]

Hereinafter, the compound of the present invention or the selected compound of the present invention means a compound represented by any one of Chemical Formulas 1 to 4 above. Specifically, the compound represented by Formula 1 is referred to as Compound 1, the compound represented by Formula 2 is referred to as Compound 2, the compound represented by Formula 3 is referred to as Compound 3, and the compound represented by Formula 4 is referred to as Compound 4.

In one aspect of the present invention, the present invention provides a compound represented by Formula A, a compound selected from pharmaceutically acceptable salts, crystalline forms, co-crystals, optical isomers, derivatives, hydrates, and solvates thereof.

Specifically, the compound may be a compound selected from compounds represented by any one of Formulas 1 to 4, pharmaceutically acceptable salts, crystal forms, co-crystals, optical isomers, derivatives, hydrates and solvates thereof.

Such pharmaceutically acceptable salts are salts generally regarded by those skilled in the art as being suitable for medical applications (eg because such salts are not detrimental to the subject being treated with the salts), or within the respective treatment It is a salt that causes acceptable side effects in Generally, the pharmaceutically acceptable salt is a salt that is considered acceptable by regulatory authorities such as the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), or the Pharmaceuticals and Medical Devices Agency (PMDA) of the Japanese Ministry of Health, Labor and Welfare. . However, the present invention in principle relates to, for example, an intermediate in the preparation of a compound according to the invention or a physiologically functional derivative thereof, or a pharmaceutically acceptable salt of a compound according to the invention or a physiologically functional derivative thereof. As intermediates in the preparation of derivatives, salts of the compounds according to the invention which are not pharmaceutically acceptable per se are also included. The salts include water-insoluble salts and, in particular, water-soluble salts.

In each case, the person skilled in the art can determine whether a particular compound according to the present invention or a physiologically functional derivative thereof can form a salt, i.e., whether said compound according to the present invention or a physiologically functional derivative thereof For example, it can be easily determined whether or not it has a group capable of carrying an electric charge, such as an amino group or a carboxylic acid group.

Exemplary salts of the compounds of the present invention are acid addition salts or salts with bases, particularly pharmaceutically acceptable inorganic and organic acid addition salts and salts with bases commonly used in pharmaceutics, which are water insoluble or particularly water soluble acid addition salts. It is salt. Depending on the substituents of the compounds of this invention, salts with bases may also be suitable. Acid addition salts are formed, for example, by combining a solution of a compound of the present invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid, or phosphoric acid. It can be formed by mixing. Likewise, pharmaceutically acceptable base addition salts include alkali metal salts (eg sodium or potassium salts); alkaline earth metal salts (eg, calcium or magnesium salts); and salts formed with suitable organic ligands (e.g., ammonium, quaternary ammonium and amines formed using counter anions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkyl sulfonates and aryl sulfonates). cations) may be included. Illustrative examples of pharmaceutically acceptable salts include acetates, adipates, alginates, arginates, ascorbates, aspartates, benzenesulfonates, benzoates, bicarbonates, bisulfates, bitartrates, borates, bromide, butyrate, calcium edetate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, citrate, digluconate, dihydrochloride, dodecylsulfate, edetate, edisylate, ethanesulfonate, Formate, fumarate, galactate, galacturonate, gluconate, glutamate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hexylresorcinate, hydrobromide, hydrochloride, hydroiodide , 2-hydroxy-ethanesulfonate, hydroxynaphthoate, iodide, isobutyrate, isothionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, mandelate, methane Sulfonate (mesylate), methyl sulfate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pantothenate, pectinate, persulfate, 3-phenylpropionate, phosphate /diphosphate, phthalate, picrate, pivalate, polygalacturonate, propionate, salicylate, stearate, sulfate, suberate, succinate, tannate, tartrate, tosylate, undecanoate, valerate and the like, but are not limited thereto.

Salts which are not pharmaceutically acceptable and which can be obtained as process products, for example during the preparation of the compounds according to the invention on an industrial scale, are also included in the present invention and, if desired, by methods known to the person skilled in the art. It can be converted into a pharmaceutically acceptable salt.

Meanwhile, since the compounds according to the present invention may have an asymmetric carbon center, they may exist as R or S isomers or racemic compounds, and all optical isomers and mixtures thereof may be included in the scope of the present invention.

In addition, the compounds of the present invention, as well as their salts, when isolated, for example in crystalline form, may contain varying amounts of solvent. Thus, solvates, especially hydrates, of the compounds of the present invention as well as solvates, particularly hydrates, of salts of the compounds of the present invention may be included within the scope of the present invention. More particularly, the present invention may include hydrates of the compounds, salts and/or physiologically functional derivatives according to the present invention comprising 1, 2 or 1/2 water molecules relative to the stoichiometry. .

Hereinafter, the compound of the present invention means the compound described above.

In another aspect of the present invention, the present invention includes as an active ingredient a compound selected from the compound represented by Formula A, a pharmaceutically acceptable salt, crystalline form, co-crystal, optical isomer, derivative, hydrate, and solvate thereof To provide a pharmaceutical composition for the prevention or treatment of cancer.

Specifically, the compound may be a compound selected from compounds represented by any one of Formulas 1 to 4, pharmaceutically acceptable salts, crystal forms, co-crystals, optical isomers, derivatives, hydrates and solvates thereof.

The cancer includes breast cancer, uterine cancer, esophageal cancer, stomach cancer, brain cancer, rectal cancer, colon cancer, lung cancer, skin cancer, ovarian cancer, cervical cancer, kidney cancer, blood cancer, pancreatic cancer, prostate cancer, testicular cancer, laryngeal cancer, oral cancer, head and neck cancer, thyroid cancer, It may be liver cancer, bladder cancer, osteosarcoma, lymphoma, leukemia, etc., but is not limited thereto, preferably lung cancer, more preferably non-small cell lung cancer. Alternatively, the cancer may be cancer in which the NRF2 protein or the gene encoding it is overexpressed compared to normal, preferably lung cancer in which the NRF2 protein or the gene encoding it is overexpressed compared to normal, more preferably the NRF2 protein, or the cancer. It may be non-small cell lung cancer in which the coding gene is overexpressed compared to normal.

The pharmaceutical composition is for the purpose of preventing or treating cancer. Prevention or treatment herein comprehensively includes activities that inhibit the formation or growth of cancer, or improve symptoms of cancer invasion, metastasis, or recurrence.

In the present invention, the pharmaceutical composition may be in the form of capsules, tablets, granules, injections, ointments, powders or beverages, and the pharmaceutical composition may be intended for humans.

The pharmaceutical composition of the present invention is not limited to these, but is formulated according to conventional methods into oral formulations such as powders, granules, capsules, tablets, aqueous suspensions, external preparations, suppositories and sterile injection solutions. can The pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers may include binders, lubricants, disintegrants, excipients, solubilizers, dispersants, stabilizers, suspending agents, pigments, flavors, etc. for oral administration, and buffers, preservatives, and painless agents for injections. A topical, solubilizing agent, isotonic agent, stabilizer, etc. may be mixed and used, and in the case of topical administration, a base, excipient, lubricant, preservative, etc. may be used. Formulations of the pharmaceutical composition of the present invention may be variously prepared by mixing with the pharmaceutically acceptable carrier as described above. For example, for oral administration, it can be prepared in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc., and in the case of injections, it can be prepared in unit dosage ampoules or multiple dosage forms. there is. In addition, it may be formulated into solutions, suspensions, tablets, capsules, sustained-release preparations, and the like.

On the other hand, examples of carriers, excipients and diluents suitable for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, malditol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil and the like can be used. In addition, fillers, anti-coagulants, lubricants, wetting agents, flavoring agents, emulsifiers, preservatives, and the like may be further included.

The route of administration of the pharmaceutical composition according to the present invention is not limited to these, but is oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical , sublingual or rectal. Oral or parenteral administration is preferred. The parenteral administration includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intrabursal, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques. The pharmaceutical composition of the present invention may also be administered in the form of a suppository for rectal administration.

The pharmaceutical composition of the present invention depends on various factors including the activity of the specific compound used, age, body weight, general health, sex, diet, administration time, route of administration, excretion rate, drug combination and severity of the specific disease to be prevented or treated. It can vary widely, and the dosage of the pharmaceutical composition varies depending on the patient's condition, body weight, disease severity, drug form, administration route and period, but can be appropriately selected by those skilled in the art, and is 0.0001 to 50 mg/day. kg or 0.001 to 50 mg/kg. Administration may be administered once a day, or may be administered in several divided doses. The dosage is not intended to limit the scope of the present invention in any way. The pharmaceutical composition according to the present invention may be formulated into a pill, dragee, capsule, liquid, gel, syrup, slurry, or suspension.

The pharmaceutical composition of the present invention may be used alone or in combination with methods using surgery, radiation therapy, hormone therapy, chemotherapy, and biological response modifiers.

In addition, the present invention provides a compound selected from the compound of the present invention, a pharmaceutically acceptable salt, crystalline form, co-crystal, optical isomer, derivative, hydrate and solvate thereof to a subject (eg, human) in need of administration as an active ingredient. It provides a method for preventing, improving or treating cancer comprising administering a pharmaceutical composition comprising a pharmaceutically effective amount. In this case, the above "administration" means providing a given compound of the present invention to a subject by any suitable method.

Specific details regarding the cancer, pharmaceutical composition, and route of administration in the method for preventing, improving, or treating cancer are described in the above “Compound of the present invention, pharmaceutically acceptable salt thereof, crystalline form, co-crystal, optical isomer, derivative , A pharmaceutical composition containing a compound selected from hydrates and solvates as an active ingredient” overlaps with what is described, and is omitted to prevent excessive complexity of the specification.

In the present invention, the "subject" in need of the administration may include both mammals and non-mammals. Here, examples of such mammals include humans, non-human primates such as chimpanzees, and other apes and monkey species; livestock animals such as cattle, horses, sheep, goats, pigs; domesticated animals such as rabbits, dogs and cats; Experimental animals, such as rodents, such as rats, mice, and guinea pigs, may be included, but are not limited thereto. In addition, examples of the non-mammals in the present invention may include birds and fish, but are not limited thereto.

In the present invention, the "pharmaceutically effective amount" refers to a sufficient amount of an agent to provide a desired biological result. The result is the reduction and/or alleviation of the signs, symptoms or causes of a disease, or any biological outcome. There may be other desired variations. For example, an "effective amount" for therapeutic use is the amount of a compound disclosed herein that is required to provide a clinically significant reduction in disease. In any individual case, an appropriate "effective amount" " Amounts can be determined by those skilled in the art using routine experimentation. Accordingly, the expression "effective amount" generally refers to an amount in which an active substance has a therapeutic effect.

In another aspect of the present invention, the present invention includes as an active ingredient a compound selected from the compound represented by Formula A, a food acceptable salt thereof, a crystalline form, a co-crystal, an optical isomer, a derivative, a hydrate, and a solvate thereof To provide a food composition for preventing or improving cancer.

Specifically, the compound may be a compound selected from a compound represented by any one of Formulas 1 to 4, a food acceptable salt thereof, a crystalline form, a co-crystal, an optical isomer, a derivative, a hydrate, and a solvate thereof.

The cancer includes breast cancer, uterine cancer, esophageal cancer, stomach cancer, brain cancer, rectal cancer, colon cancer, lung cancer, skin cancer, ovarian cancer, cervical cancer, kidney cancer, blood cancer, pancreatic cancer, prostate cancer, testicular cancer, laryngeal cancer, oral cancer, head and neck cancer, thyroid cancer, It may be liver cancer, bladder cancer, osteosarcoma, lymphoma, leukemia, etc., but is not limited thereto, preferably lung cancer, more preferably non-small cell lung cancer. Alternatively, the cancer may be cancer in which the NRF2 protein or the gene encoding it is overexpressed compared to normal, preferably lung cancer in which the NRF2 protein or the gene encoding it is overexpressed compared to normal, more preferably the NRF2 protein, or the cancer. It may be non-small cell lung cancer in which the coding gene is overexpressed compared to normal.

The food composition is for the purpose of preventing or improving cancer. Prevention or improvement herein comprehensively includes activities that inhibit the generation or growth of cancer, or improve symptoms of cancer invasion, metastasis, or recurrence.

In the present invention, the food composition is used in various ways for the purpose of the present invention, that is, the prevention or improvement of cancer, and the food composition containing the compound of the present invention is various foods, such as beverages, It can be manufactured in the form of gum, tea, vitamin complex, powder, granule, tablet, capsule, confectionery, rice cake, bread, etc. When the composition of the present invention is included in a food composition, the amount may be added in an amount of 0.1 to 100% of the total weight. Here, when the food composition is prepared in the form of a beverage, there is no particular limitation except that the food composition is contained in the indicated ratio, and various flavors or natural carbohydrates may be included as additional ingredients as in conventional beverages. In other words, natural carbohydrates include monosaccharides such as glucose, disaccharides such as fructose, polysaccharides such as sucrose, and common sugars such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. can do. Examples of the flavoring agent include natural flavoring agents (thaumatin, stevia extract (eg, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.). Others of the present invention The food composition of is various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, colorants, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, Stabilizers, preservatives, glycerin, alcohol, carbonation agents used in carbonated beverages, etc. These components may be used independently or in combination The ratio of these additives is usually per 100 parts by weight of the composition of the present invention It is generally selected from the range of 0.1 to 100 parts by weight, but is not limited thereto.

In another aspect of the present invention, the present invention is NRF2 (Nuclear factor erythroid) comprising a compound represented by Formula A, a compound selected from salts, crystal forms, co-crystals, optical isomers, derivatives, hydrates, and solvates thereof. A 2-related factor 2) protein or an expression inhibitor of a gene encoding the same is provided.

Specifically, the compound may be a compound selected from compounds represented by any one of Formulas 1 to 4, salts, crystal forms, co-crystals, optical isomers, derivatives, hydrates and solvates thereof.

The compound has an effect of suppressing the expression of NRF2 (Nuclear factor erythroid 2-related factor 2) protein or a gene encoding the same. The NRF2 protein is a transcription factor encoded by the NFE2L2 gene and is a basic leucine zipper (bZIP) protein capable of regulating the expression of antioxidant proteins to protect cells from oxidative damage caused by injury and inflammation. As part of a complex homeostatic regulatory network, it plays a versatile role in the regulation of metabolism, inflammation, autophagy, proteostasis, mitochondrial physiology, and the immune response. Cancer is generally characterized by a hypoxic environment. It is known that NRF2 is activated in intractable cancers with multiple mutations and low drug response, such as non-small cell lung cancer, and suppression of NRF2 expression effectively inhibits the growth of cancer cells. Inhibition is known through prior art documents in the art to which the present invention pertains.

Hereinafter, the present invention will be described in detail based on examples.

Since the compound provided in the present invention exhibits high reactivity to intractable lung cancer, it is expected to be actively used in the medical and health fields.

Figure 1 shows the excellent anticancer effect of the compounds selected in the present invention compared to the negative control group according to one embodiment of the present invention.
Figure 2 shows the excellent anticancer effect of the compounds selected in the present invention compared to the positive control group according to one embodiment of the present invention.

Hereinafter, the present invention will be described in more detail through examples. These examples are only for explaining the present invention in more detail, and it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples according to the gist of the present invention. .

Example 1: Anti-cancer compound screening

The inventors of the present invention screened various candidate substances to discover cancer cell and/or cancer stem cell treatment substances having anticancer activity, and as a result, derived indazolyl ester and amide compounds of the following formula A as anticancer candidates, Among the derivatives, 4 types (Formulas 1 to 4) with expected effects were selected.

[Formula A]

[Formula 1]

[Formula 2]

[Formula 3]

[Formula 4]

Hereinafter, the compound represented by Formula 1 is referred to as Compound 1, the compound represented by Formula 2 as Compound 2, the compound represented by Formula 3 as Compound 3, and the compound represented by Formula 4 as Compound 4.

Example 2: Confirmation of anticancer effect of selected compounds

For use in the experiment, non-small-cell lung carcinoma (NSCLC) H1299 or A549 cells were purchased from the Korea Cell Line Bank, 10% fetal bovine serum (FBS, Invitrogen), 1% penicillin. - Streptomycin and 1% HEPES were supplemented with DMEM culture medium (HyClone Laboratories, USA), 5% CO ₂ , and cultured at 37°C. Dimethyl sulfoxide (DMSO) as a negative control for compounds 1 to 4 selected in the present invention and dexamethasone acetate (DEXA) as a positive control were purchased from Sigma-Aldrich (St. Louis, USA) and used.

In non-small cell lung cancer, mutations in KEAP1 (Kelch-like ECH-associated protein 1) and STK11 (serine/threonine kinase 11) genes are common, and KEAP1 mutation activates NRF2 (Nuclear factor erythroid 2-related factor 2) , and therefore, it is known through conventionally known documents in the art that the growth of cancer cells is effectively inhibited when the expression of NRF2 is inhibited in non-small cell lung cancer. Therefore, the anticancer effect of the compounds selected in the present invention was confirmed by inhibiting NRF2 expression. To this end, after seeding 5×10 ⁶ cells in a 6-well plate, they were cultured for 24 hours in DMEM medium containing 1nM, 10nM, or 100nM of each compound. Thereafter, the supernatant was removed, washed with PBS, and the cells were collected and lysed with a cell lysis buffer (Cell signaling technology) supplemented with a protease inhibitor cocktail (EMD millipore) to prepare a protein extract for western blotting. After electrophoresis, 10 μg of each separated protein was loaded on an 8% acrylamide gel, transferred to a nitrocellulose (NC) membrane, and NRF2 antibody (Cell signaling, 1:1000) and actin ) antibody (SCBT, 1:1000) was diluted in TBST (Tris-Buffered Saline with tween 20) buffer containing 5% skim milk and reacted overnight at 4°C. After that, the secondary antibody (Cell Signaling Technology) was reacted for 1 hour, washed with TBST, and the protein expression level was measured using ECL (Enhanced chemiluminescence). The results are shown in Figures 1 and 2.

Referring to Figure 1, all of the compounds 1 to 4 of the present invention had a significant anticancer effect compared to the negative control group. In particular, in the case of compounds 1 to 3, NRF2 expression was suppressed by more than 50% even at low concentrations (1 nM), showing very high reactivity to cancer cells. However, in the case of compound 4, the reactivity was relatively insufficient at a low concentration (1 nM) compared to compounds 1 to 3, and it was found that both indazolyl ester and amide derivatives did not exhibit equally effective anticancer activity.

Also, referring to FIG. 2, Compounds 2 and 3 of the present invention had equal or superior anticancer effects compared to the positive control group (DEXA).

Having described specific parts of the present invention in detail above, it is clear that these specific techniques are merely preferred embodiments for those skilled in the art, and the scope of the present invention is not limited thereto. Accordingly, the substantial scope of the present invention will be defined by the appended claims and equivalents thereof.

Claims (12)

A pharmaceutical composition for preventing or treating cancer comprising a compound represented by Formula A below or a pharmaceutically acceptable salt thereof as an active ingredient,
[Formula A]

The cancer is non-small cell lung cancer,
The compound represented by Formula A is a compound represented by Formula 2 or a compound represented by Formula 3, a pharmaceutical composition:
[Formula 2]

[Formula 3]
.
delete delete delete delete delete delete According to claim 1,
The cancer is a pharmaceutical composition in which NRF2 (Nuclear factor erythroid 2-related factor 2) protein, or a gene encoding it, is overexpressed compared to normal.
According to claim 1,
The cancer treatment is to inhibit the proliferation of cancer, or inhibit the metastasis of cancer, the pharmaceutical composition.
According to claim 1,
The pharmaceutical composition may be an oral dosage form of a powder, granule, capsule, tablet, powder or aqueous suspension; external use; suppositories; Or a sterile injectable solution; to be prepared in the form of, a pharmaceutical composition.
A food composition for preventing or improving cancer comprising a compound represented by Formula A below, or a pharmaceutically acceptable salt thereof,
[Formula A]

The cancer is non-small cell lung cancer,
The compound represented by Formula A is a compound represented by Formula 2 or a compound represented by Formula 3, a food composition:
[Formula 2]

[Formula 3]
.
A compound represented by the following formula A, or a pharmaceutically acceptable salt thereof, for inhibiting the expression of NRF2 (Nuclear factor erythroid 2-related factor 2) protein in cells in vitro or a gene encoding the same As a composition,
[Formula A]

The cells are non-small cell lung cancer cells,
The compound represented by Formula A is a compound represented by Formula 2, or a compound represented by Formula 3, expression inhibition composition:
[Formula 2]

[Formula 3]
.