Composition for treating fibrosis

Abstract

The p300 inhibitor specifically regulates the expression of genes that induce fibrosis, thereby acting only on fibrotic tissues and reducing the risk of adverse effects on normal tissues. Because the inhibitor blocks multiple fibrotic signaling pathways, it may be effective for fibrosis in various organs such as the liver, lungs, and kidneys. In addition, by modulating gene expression, the inhibitor has the potential to address the fundamental cause of the fibrotic process. The present invention is characterized in that bronopol is first identified as a specific example of such a p300 inhibitor. In particular, bronopol is an FDA-approved drug with established safety, and therefore is expected to reduce the time and cost required for conducting clinical trials.

Description

Composition for treating fibrosis

[0001] The present invention relates to innovative new drugs and next-generation biopharmaceuticals, and more specifically, to an advanced biopharmaceutical composition for treating fibrosis developed using ICT-based new drug development platform technology.

[0002] Fibrosis is the abnormal accumulation of collagen matrix following injury or inflammation, altering the structure and function of various tissues. Regardless of the site of origin, the pathogenesis of fibrosis is largely driven by the excessive accumulation of fibrous connective tissue, such as collagen matrix, replacing normal tissue. Progressive fibrosis in the kidneys, liver, fat, lungs, heart, bone or bone marrow, and skin is a major cause of death and suffering. Pulmonary fibrosis, in particular, is a disease in which chronic inflammatory cells infiltrate the alveolar walls of lung tissue, inducing tissue fibrosis and causing severe structural changes in lung tissue. It is a fibrotic disease that causes severe respiratory distress due to the hardening of lung tissue. Idiopathic pulmonary fibrosis is a type of interstitial pneumonia characterized by progressive fibrosis of the lung parenchyma and is known to have the poorest prognosis. The cause of idiopathic pulmonary fibrosis is not yet clearly known, but smoking, viral infections, environmental toxins, or a family history are believed to be triggers (Am J Manag Care. 2017 Jul;23(11 Suppl):S176-S182.). Clinical symptoms include dyspnea on exercise and a cough that is usually not accompanied by sputum, which gradually increases. Since the human lung has a large amount of spare lung capacity, allowing people to live without major discomfort even if one lung is removed, it is difficult for patients with pulmonary fibrosis to recognize the symptoms, so it is often diagnosed after the symptoms have worsened.

[0003] Treatment options for pulmonary fibrosis detected in its early stages include steroids, such as azathioprine, and cyclophosphamide; antioxidants, such as acetylcysteine; and growth factors, such as the cytokine IFN-γ. While numerous studies and reports have been conducted on steroids and antioxidants since 2000, their efficacy has not yet been proven. Long-term administration has been reported to cause systemic side effects or the development of drug resistance. Once pulmonary fibrosis progresses to full-blown fibrosis, no medication is effective. Therefore, active research has been conducted on methods that directly modulate transcription factors that play a role in transcriptional activity to more effectively treat pulmonary fibrosis. However, currently, few medications are approved as treatments for pulmonary fibrosis. Since the best way is to diagnose pulmonary fibrosis early, before it has progressed significantly, and prevent it from progressing completely to pulmonary fibrosis, there is an urgent need to develop treatments that can prevent pulmonary fibrosis before it occurs, as well as treatments that can treat it after it occurs.

[0004] One object of the present invention is to provide a pharmaceutical composition for treating or preventing fibrosis, comprising a p300 inhibitor as an active ingredient.

[0005] Another object of the present invention is to provide a food composition for improving or preventing fibrosis, comprising a p300 inhibitor as an active ingredient.

[0006] Another object of the present invention is to provide a cosmetic composition for improving or preventing fibrosis, comprising a p300 inhibitor as an active ingredient.

[0007] However, the technical problems to be solved by the present invention are not limited to the problems mentioned above, and other problems not mentioned can be clearly understood by those skilled in the art from the description below.

[0008] Various embodiments of the present invention are described with reference to the drawings. In the following description, various specific details, such as specific configurations, compositions, and processes, are set forth to provide a thorough understanding of the present invention. However, certain embodiments may be practiced without one or more of these specific details, or in conjunction with other known methods and configurations. In other instances, well-known processes and manufacturing techniques are not described in specific detail so as not to unnecessarily obscure the present invention. Reference throughout this specification to an embodiment means that a particular feature, configuration, composition, or characteristic described in connection with the embodiment is included in one or more embodiments of the present invention. Thus, the appearance of an embodiment in various places throughout this specification does not necessarily indicate the same embodiment of the present invention. Additionally, the particular features, configurations, compositions, or characteristics may be combined in any suitable manner in one or more embodiments.

[0009] In one embodiment of the present invention, a pharmaceutical composition for treating or preventing fibrosis is provided, comprising a p300 inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient.

[0010] In the present invention, the pharmaceutically acceptable salt may include an acid or base addition salt. For example, the compound may be in the form of an organic or inorganic acid addition salt. The salt may include, but is not limited to, any salt that has a desired effect on the patient when administered to the patient and maintains the activity of the parent compound. These salts include inorganic and organic salts, such as acetic acid, nitric acid, aspartic acid, sulfonic acid, sulfuric acid, maleic acid, glutamic acid, formic acid, succinic acid, phosphoric acid, phthalic acid, tannic acid, tartaric acid, hydrobromic acid, propionic acid, benzenesulfonic acid, benzoic acid, stearic acid, lactic acid, bicarboxylic acid, bisulfuric acid, bitartaric acid, oxalic acid, butyric acid, calcium idet, carbonic acid, chlorobenzoic acid, citric acid, idetic acid, toluenesulfonic acid, fumaric acid, gluceptic acid, esilic acid, pamoic acid, gluconic acid, methyl nitrate, malonic acid, hydrochloric acid, hydroiodoic acid, hydroxynaphtholic acid, isethionic acid, lactobionic acid, mandelic acid, mucic acid, napsylic acid, muconic acid, p-Nitromethanesulfonic acid, hexamic acid, pantothenic acid, nohydrogenphosphoric acid, dihydrogenphosphoric acid, salicylic acid, sulfamic acid, sulfanilinic acid, methanesulfonic acid, etc. The addition salts of bases may include salts of alkali metals or alkaline earth metals, such as salts of ammonium, lithium, sodium, potassium, magnesium, calcium, etc.; salts with organic bases, such as salts of benzathine, N-methyl-D-glucamine, hydrabamine, etc.; and salts with amino acids, such as arginine, lysine, etc. In addition, these salts can be converted into free forms by treatment with an appropriate base or acid.

[0011] In the present invention, the above-mentioned “p300”, “histone acetyltransferase p300”, is also known as p300 HAT or E1A-related protein p300 (E1A = adenovirus early region 1A), and the enzyme, also known as EP300 or p300, is encoded by the EP300 gene in humans. It also acts as a histone acetyltransferase that regulates gene transcription through chromatin remodeling by making histone proteins less tightly wrap around DNA. This enzyme plays an essential role in regulating cell growth and division, promoting cell maturation and specialized function performance (differentiation), and preventing the growth of cancerous tumors. The EP300 gene is located at position 13.2 of the long (q) arm of human chromosome 22. This gene encodes the adenovirus E1A-related cellular p300 transcriptional co-activator protein.

[0012] In the present invention, the “p300 inhibitor” includes any compound, protein or nucleotide that inhibits the function or expression of p300, and includes, for example, any compound, protein or nucleotide that inhibits the function or expression of p300, including a compound including a small molecule, an antibody, a protein including an enzyme, or siRNA, an oligonucleotide.

[0013] In another embodiment of the present invention, a pharmaceutical composition is provided wherein the p300 inhibitor is a p300 histone acetyl-transferase inhibitor.

[0014] The composition of the present invention is characterized by a remarkably excellent inhibitory effect on fibrosis-related diseases that have developed or are likely to develop in an individual by inhibiting the activity of histone acetyl-transferase (HAT).

[0015] In the present invention, the "histone acetylase" is an enzyme that acetylates histone substrates, thereby exerting important regulatory effects on chromatin structure and assembly, as well as gene transcription. Modification of these proteins by HATs plays a crucial role in the regulation of gene expression, and its dysregulation is known to cause cancer, neurodegeneration, and various other diseases. Examples of diseases associated with dysregulation of histone deacetylase activity include neoplastic diseases, Huntington's disease caused by triplet amplification, degenerative diseases, ischemia, oxidative stress, inflammatory reactions in the nervous system, epilepsy, diseases caused by protein aggregates, HIV infection, malaria, leishmaniasis, infections caused by protozoa, fungi, phytotoxic agents, viruses and parasites, autoimmune diseases, chronic host-directed immune reactions, hypertrophy and heart diseases, fibrotic skin diseases, spinal and bulbar muscular atrophy, bipolar disorder, psychiatric disorders, X-fragile syndrome, arthritis, kidney diseases, These include psoriasis, intestinal-colitis disease, beta thalassemia, respiratory diseases, and Rubinstein-Taybi syndrome.

[0016] In another embodiment of the present invention, a pharmaceutical composition is provided, wherein the p300 histone acetyl-transferase inhibitor is at least one selected from the group consisting of GNE-781, SGC-CBP30, CPI-637, NEO2734, CPI-637, A-485, PF-CBP1 HCl, I-CBP112, C646, EML 425, YF-2, ICG-001, Anacardic Acid, Curcuminm, PRI-724, Nordihydroguaiaretic acid (NDGA), NEO2734, and Bronopol.

[0017] In another embodiment of the present invention, a pharmaceutical composition is provided, wherein the p300 histone acetyl-transferase inhibitor is Bronopol represented by the following chemical formula 1.

[0018] [Chemical Formula 1]

[0019]

[0020] The molecular weight of the above Bronopol is 199.99, the chemical formula is represented by C3H6BrNO4, and the structural formula is C(C(CO)([N+](=O)[O-])Br)O.

[0021] Bronopol, as mentioned above, is widely used as a preservative or antibacterial agent in consumer products such as shampoos and cosmetics due to its high activity against bacteria, especially Gram-negative bacteria. Bronopol is particularly widely used in cosmetics and toiletries, but its use in the treatment of fibrosis has not been fully elucidated.

[0022] In another embodiment of the present invention, a pharmaceutical composition is provided, wherein the fibrosis is at least one selected from the group consisting of pulmonary fibrosis, uterine fibroids, myelofibrosis, liver fibrosis, heart fibrosis, multiple sclerosis, kidney fibrosis, cystic fibrosis, neutropenia, skeletal muscle fibrosis, scleroderma, dermatomyositis, mediastinal fibrosis, and splenic fibrosis due to sickle cell anemia.

[0023] In another embodiment of the present invention, a pharmaceutical composition is provided, wherein the pulmonary fibrosis is at least one selected from the group consisting of idiopathic pulmonary fibrosis, nonspecific interstitial pneumonia, acute interstitial pneumonia, cryptogenic organizing pneumonia, respiratory bronchiolitis-associated interstitial lung, desquamative interstitial pneumonia, lymphoid interstitial pneumonia, interstitial pulmonary fibrosis, and diffuse pulmonary fibrosis.

[0024] In another embodiment of the present invention, the pharmaceutical composition is provided for oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual or rectal administration.

[0025] In the present invention, the "subject" is a mammal including a human, and may be selected from the group consisting of, for example, a human, a rat, a mouse, a guinea pig, a hamster, a rabbit, a monkey, a dog, a cat, a cow, a horse, a pig, a sheep, and a goat, and is preferably a human, but is not limited thereto.

[0026] In the pharmaceutical composition of the present invention, the disease to be prevented or treated, "fibrotic diseases" or "fibrosis" that have developed or are likely to develop in an individual, are diseases in which abnormal production, accumulation and deposition of extracellular matrix by fibroblasts occur, and any organ in which collagen matrix can be abnormally accumulated due to damage or inflammation that can change the structure and function of various tissues can include fibrosis of any organ, and preferably, fibrosis that has developed in at least one organ selected from the group consisting of kidney, liver, lung, heart, bone, bone marrow and skin, but is not limited thereto.

[0027] For the purpose of the present invention, the fibrosis may be induced by a phenomenon in which the expression of genes related to fibrosis, such as collagen, is promoted by TGF-β (Transforming growth factor-β) whose expression level is increased through p300, an acetylase, or may be induced by the absence of an enzyme capable of recovering cells from damage that may induce fibrosis, but is not limited thereto. Therefore, the p300 inhibitor, which is an acetylase provided in the present invention, suppresses the function of p300 and thereby suppresses the promotion of expression of genes related to fibrosis by TGF-β, thereby exhibiting preventive and therapeutic effects not only on lung or kidney fibrosis but also on all types of fibrosis induced by the promotion of expression of genes related to fibrosis by TGF-β.

[0028] The fibrosis of the present invention may be at least one selected from the group consisting of pulmonary fibrosis, uterine fibroids, myelofibrosis, liver fibrosis, heart fibrosis, multiple sclerosis, kidney fibrosis, cystic fibrosis, neutropenia, skeletal muscle fibrosis, scleroderma, dermatomyositis, mediastinal fibrosis, and splenic fibrosis due to sickle cell anemia, and may preferably be pulmonary fibrosis or kidney fibrosis, but is not limited thereto.

[0029] In one specific example of the present invention, the pulmonary fibrosis is a type of respiratory disease that causes serious respiratory difficulties due to hardening of lung tissue, and is a chronic disease that causes swelling and scarring of the alveoli and interstitial tissue of the lungs. It is the development of scarred (fibrous) tissue due to the formation or development of excessive fibrous connective tissue (fibrosis) in the lungs, and such scar tissue replaces healthy tissue, causing inflammation, and chronic inflammation can be considered a precursor to fibrosis. It is a disease characterized by diffuse fibrous proliferation in the alveolar walls and coughing or shortness of breath as the main symptoms. As fibrosis progresses and the lung walls thicken, the amount of oxygen supplied to the blood decreases, causing the patient to feel persistent shortness of breath.

[0030] In the present invention, pulmonary fibrosis narrowly refers to the terminal form of interstitial pneumonia, but broadly refers to the coexistence of pulmonary fibrosis and interstitial pneumonia. Any type of interstitial pneumonia can cause pulmonary fibrosis. Interstitial pneumonia is a general term for diseases that cause inflammation in the interstitium of the lungs, and includes specific causes such as infection, collagen disease, radiation, drugs, and dust, as well as idiopathic interstitial pneumonia of unknown cause. Idiopathic interstitial pneumonia is classified into idiopathic pulmonary fibrosis (IPF), nonspecific interstitial pneumonia (NSIP), acute interstitial pneumonia (AIP), cryptogenic organizing pneumonia (COP), respiratory bronchiolitis-associated interstitial lung disease (RB-ILD), desquamative interstitial pneumonia (DIP), and lymphoid interstitial pneumonia (LIP) based on findings from thoracoscopic ultrasound-guided lung biopsy (VATS) or high-resolution computed tomography (HRCT).

[0031] In the present invention, pulmonary fibrosis may be idiopathic pulmonary fibrosis, nonspecific interstitial pneumonia, acute interstitial pneumonia, idiopathic organizing pneumonia, respiratory bronchiolitis-associated interstitial lung, desquamative interstitial pneumonia, lymphoid interstitial pneumonia, interstitial pulmonary fibrosis, and diffuse pulmonary fibrosis, and preferably, idiopathic pulmonary fibrosis, but is not limited thereto.

[0032] The pulmonary fibrosis of the present invention may be caused by various causes, for example, micro-damage to the lungs induced by inhalation of fine particles (asbestos, stone dust, metal dust, particles present in cigarette smoke, silica dust, etc.). In addition, pulmonary fibrosis may occur as a secondary effect of other diseases (autoimmune diseases, viral or bacterial infections, etc.), and may be induced by specific drugs such as cytotoxic agents (bleomycin, busulfan, and methotrexate, etc.); antibiotics (nitrofurantoin and sulfasalazine, etc.); antiarrhythmic agents (amiodarone and tocainide, etc.); anti-inflammatory drugs (gold and penicillamine, etc.); and illicit drugs (narcotics, cocaine, and heroin, etc.). In the case of the idiopathic pulmonary fibrosis, it may appear due to unknown causes other than the above causes.

[0033] In another specific example of the present invention, renal fibrosis is a chronic kidney disease caused by the accumulation of extracellular matrix in the kidney, which leads to a decline in renal function or, in severe cases, loss of renal function (renal insufficiency). It is caused by the formation or development of excessive fibrous connective tissue (fibrosis) in the kidney. In the present invention, renal fibrosis may be accompanied by an inflammatory response due to endothelial cell damage, resulting in fibrosis in the excessively produced extracellular matrix (ECM).

[0034] In the present invention, renal fibrosis may correspond to glomerulosclerosis, diabetic renal fibrosis, tubulointerstitial fibrosis, hypertensive renal fibrosis, etc., but is not limited thereto as long as it corresponds to a disease that causes fibrosis in renal tissue.

[0035] In the present invention, the factor involved in the fibrosis may be one or more genes selected from the group consisting of ACTA2 (actin alpha 2; alpha smooth muscle actin; α-SMA), COL1A1 (alpha-1 type I collagen), FN1 (fibronectin 1), COL3A1 (alpha-1 type III collagen), CTGF (connective tissue growth factor), Vimentin, etc., or a protein encoded by the same, but is not limited thereto.

[0036] In the present invention, the ACTA2 is a protein also called alpha-smooth muscle actin (α-SMA), which belongs to a multifunctional protein family that forms microfilaments. ACTA2 corresponds to one of six actin isoforms, is involved in the contractile process of smooth muscle, and is found in almost all mammals. When a mutation occurs in the ACTA2 gene, it causes various vascular diseases such as thoracic aortic disease, coronary artery disease, stroke, and multi-organ smooth muscle dysfunction syndrome. In addition, the ACTA2 is commonly called α-SMA, which is mainly used in the study of anti-fibrotic effects and fibrosis mechanisms as a marker of myofibroblast formation. In particular, the de novo synthesis of α-SMA transforms lung fibroblasts into a myofibroblast phenotype, and is upregulated in areas where lung fibrosis progresses, and is known to play a major role in the development and progression of lung fibrosis.

[0037] In the present invention, the COL1A1 encodes the pro-alpha 1 chain of type I collagen, which comprises two alpha 1 chains and one alpha 2 chain in a triple helix structure. Type I is a fibril-forming collagen found in most connective tissues and is known to be abundant in bone, cornea, dermis, and tendon. When a mutation occurs in the gene, it causes osteogenesis imperfecta types I-IV, Ehlers-Danlos syndrome type VIIA, Ehlers-Danlos syndrome Classical type, Caffey Disease, and idiopathic osteoporosis.

[0038] In the present invention, the COL3A1 is a protein composed of a homotrimer or three identical peptide chains (monomers), each of which is also called the alpha 1 chain of type III collagen. Officially, this monomer is called type III collagen, alpha 1 chain, and in humans, it is encoded by the COL3A1 gene. Type III collagen is one of the fibrillar collagens in which the protein has a long, inflexible triple helical domain. Increased levels of the COL3A1 are found in many fibrotic conditions, such as liver and kidney fibrosis and systemic sclerosis. This has led to a search for serum biomarkers that can be used to diagnose these conditions without undergoing a tissue biopsy. The most widely used biomarker is the N-terminal propeptide of type III procollagen, which is cleaved during the biosynthesis of type III collagen.

[0039] In the present invention, the CTGF or CCN2, also known as connective tissue growth factor, is a parental protein of the CCN family of extracellular matrix-associated heparin-binding proteins. CTGF plays a crucial role in many biological processes, including cell adhesion, migration, proliferation, angiogenesis, skeletal development, and tissue wound healing, and plays a significant role in fibrotic diseases and various forms of cancer. In particular, CTGF is associated with wound healing and virtually all fibrotic pathologies. CTGF is thought to induce persistent fibrosis in cooperation with TGF-β and may exacerbate extracellular matrix production in association with other pro-fibrotic conditions. Overexpression of CTGF in fibroblasts promotes fibrosis in the dermis, kidney, and lung, and deletion of CTFG in fibroblasts and smooth muscle cells significantly reduces bleomycin-induced skin fibrosis.

[0040] In the present invention, the FN1 encodes fibronectin, a glycoprotein that exists in the form of a soluble dimer in plasma and in dimers or multimers on the cell surface and extracellular matrix. Fibronectin is well known to be involved in cell adhesion and migration processes, including embryogenesis, wound healing, blood coagulation, host defense, and metastasis.

[0041] In the present invention, Vimentin is a structural protein encoded by the human VIM gene. Its name is derived from the Latin word vimentum, which refers to a flexible rod-like arrangement. Vimentin is a type III intermediate filament (IF) protein expressed in the mesenchyme.

[0042] In one specific example of the present invention, transforming growth factor β (TGF-β) is the main TGF-β isoform produced by bronchial epithelial cells and fibroblasts in normal lung tissue, and is a major factor inducing epithelial-mesenchymal transition (EMT), and is known to induce α-SMA de novo synthesis during this process and change the phenotype of epithelial cells into myofibroblasts. Since fibronectin secretion and α-SMA are upregulated by TGF-β, it is mainly used to study the mechanism of tissue fibrosis.

[0043] The composition of the present invention can be used for, but is not limited to, a pharmaceutical composition, a food composition, or a cosmetic composition.

[0044] In the present invention, “prevention” may include, without limitation, any act of blocking symptoms caused by fibrosis or suppressing or delaying symptoms of respiratory diseases using the composition of the present invention.

[0045] In the present invention, “improvement” may include without limitation any act in which symptoms caused by fibrosis are alleviated or reduced, or symptoms that have been worsened are improved or beneficially changed, by ingesting or examining the composition of the present invention.

[0046] In the present invention, “treatment” may include, without limitation, any act that improves or benefits symptoms caused by fibrosis by using the composition of the present invention.

[0047] In the present invention, the pharmaceutical composition may be characterized as being in the form of a capsule, tablet, granule, injection, ointment, powder or beverage, and the pharmaceutical composition may be characterized as being for human use.

[0048] The pharmaceutical composition of the present invention is not limited to these, but can be formulated and used in the form of oral dosage forms such as powders, granules, capsules, tablets, aqueous suspensions, etc., external preparations, suppositories, and sterile injection solutions, respectively, according to conventional methods. 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, coloring agents, fragrances, etc. for oral administration, and buffers, preservatives, analgesics, solubilizers, isotonic agents, stabilizers, etc. for injections. In the case of topical administration, bases, excipients, lubricants, preservatives, etc. can be used. The formulation of the pharmaceutical composition of the present invention can be prepared in various ways by mixing it with the pharmaceutically acceptable carriers described above. For example, for oral administration, it can be manufactured in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc., and for injections, it can be manufactured in the form of unit dose ampoules or multiple doses. In addition, it can be formulated in the form of solutions, suspensions, tablets, capsules, sustained-release preparations, etc.

[0049] Meanwhile, 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, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, or mineral oil. In addition, fillers, anticoagulants, lubricants, wetting agents, fragrances, emulsifiers, preservatives, and the like may be additionally included.

[0050] Routes of administration of the pharmaceutical composition according to the present invention include, but are not limited to, oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, or rectal. Oral or parenteral administration is preferred.

[0051] In the present invention, "parenteral" includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intrasynovial, 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.

[0052] The pharmaceutical composition of the present invention may vary depending on various factors including the activity of the specific compound used, age, body weight, general health, sex, dosage form, administration time, administration route, excretion rate, drug combination, and the severity of the specific disease to be prevented or treated, and the dosage of the pharmaceutical composition may vary depending on the patient's condition, body weight, degree of disease, pharmaceutical form, administration route, and period, but may be appropriately selected by those skilled in the art, and may be administered at 0.0001 to 50 mg / kg or 0.001 to 50 mg / kg per day. Administration may be administered once a day or divided into several times. The dosage does not limit the scope of the present invention in any way. The pharmaceutical composition according to the present invention may be formulated as a pill, a sugar-coated tablet, a capsule, a liquid, a gel, a syrup, a slurry, or a suspension.

[0053] In one embodiment of the present invention, a food composition for improving or preventing fibrosis is provided, comprising a p300 inhibitor as an active ingredient.

[0054] In another embodiment of the present invention, a food composition is provided, wherein the p300 inhibitor is a p300 histone acetyl-transferase inhibitor.

[0055] In another embodiment of the present invention, a food composition is provided, wherein the p300 histone acetyl-transferase inhibitor is at least one selected from the group consisting of GNE-781, SGC-CBP30, CPI-637, NEO2734, CPI-637, A-485, PF-CBP1 HCl, I-CBP112, C646, EML 425, YF-2, ICG-001, Anacardic Acid, Curcuminm, PRI-724, Nordihydroguaiaretic acid (NDGA), NEO2734, and Bronopol.

[0056] In another embodiment of the present invention, a food composition is provided, wherein the p300 histone acetyl-transferase inhibitor is represented by the following chemical formula 1.

[0057] [Chemical Formula 1]

[0058]

[0059] In another embodiment of the present invention, a food composition is provided, wherein the fibrosis is at least one selected from the group consisting of pulmonary fibrosis, uterine fibroids, myelofibrosis, liver fibrosis, heart fibrosis, multiple sclerosis, kidney fibrosis, cystic fibrosis, neutropenia, skeletal muscle fibrosis, scleroderma, dermatomyositis, mediastinal fibrosis, and splenic fibrosis due to sickle cell anemia.

[0060] In another embodiment of the present invention, a food composition is provided, wherein the pulmonary fibrosis is at least one selected from the group consisting of idiopathic pulmonary fibrosis, nonspecific interstitial pneumonia, acute interstitial pneumonia, cryptogenic organizing pneumonia, respiratory bronchiolitis-associated interstitial lung, desquamative interstitial pneumonia, lymphoid interstitial pneumonia, interstitial pulmonary fibrosis, and diffuse pulmonary fibrosis.

[0061] In the present invention, the food composition is used in various ways to prevent or improve the indications aimed at in the present invention, and the food composition containing the composition of the present invention as an active ingredient can be manufactured in the form of various foods, for example, beverages, gum, tea, vitamin complexes, powders, granules, tablets, capsules, confectionery, rice cakes, bread, etc. Since the food composition of the present invention is configured by improving existing food ingestibles with almost no toxicity and side effects, it can be used with confidence even when taken for a long period of time for preventive purposes. When the composition of the present invention is included in a food composition, the amount can be added at a ratio of 0.1 to 100% of the total weight. Here, when the food composition is manufactured in the form of a beverage, there is no special limitation other than containing the food composition at the indicated ratio, and various flavoring agents or natural carbohydrates, etc. can be contained as additional ingredients like conventional beverages. That is, it may include natural carbohydrates such as monosaccharides such as glucose, disaccharides such as fructose, sucrose, polysaccharides, dextrin, cyclodextrin, and common sugars, and sugar alcohols such as xylitol, sorbitol, and erythritol. Examples of the flavoring agent include natural flavoring agents (thaumatin, stevia extracts (e.g., rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.). In addition, the food composition of the present invention may contain various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavoring agents and natural flavoring agents, coloring agents, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloid thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc. These components may be used independently or in combination. The ratio of such additives is typically selected in the range of 0.1 to 100 parts by weight per 100 parts by weight of the composition of the present invention, but is not limited thereto.

[0062] In one embodiment of the present invention, a cosmetic composition for improving or preventing fibrosis is provided, comprising a p300 inhibitor as an active ingredient.

[0063] In another embodiment of the present invention, a cosmetic composition is provided, wherein the p300 inhibitor is a p300 histone acetyl-transferase inhibitor.

[0064] In another embodiment of the present invention, a cosmetic composition is provided, wherein the p300 histone acetyl-transferase inhibitor is at least one selected from the group consisting of GNE-781, SGC-CBP30, CPI-637, NEO2734, CPI-637, A-485, PF-CBP1 HCl, I-CBP112, C646, EML 425, YF-2, ICG-001, Anacardic Acid, Curcuminm, PRI-724, Nordihydroguaiaretic acid (NDGA), NEO2734, and Bronopol.

[0065] In another embodiment of the present invention, a cosmetic composition is provided, wherein the p300 histone acetyl-transferase inhibitor is represented by the following chemical formula 1.

[0066] [Chemical Formula 1]

[0067]

[0068] In another embodiment of the present invention, a cosmetic composition is provided wherein the fibrosis is scleroderma.

[0069] In the present invention, the "scleroderma" is a chronic connective tissue disease of unknown etiology characterized by sclerotic changes in which the skin hardens and thickens in part or the entire body due to excessive accumulation of collagen in the dermis, as well as vascular abnormalities. Bronopol, represented by Chemical Formula 1 provided in the present invention, specifically regulates gene expression that induces fibrosis and acts only on fibrotic tissue, thereby reducing the risk of side effects on normal tissue. In addition, since it blocks various fibrotic signaling pathways, it can effectively improve or prevent not only fibrosis but also scleroderma, an example of fibrosis. In addition, there is a possibility that the fundamental cause of the fibrotic process can be treated by regulating gene expression.

[0070] In the present invention, the cosmetic composition may be manufactured in the form of a toner, a nutritional lotion, a nutritional essence, a massage cream, a cosmetic bath additive, a body lotion, a body milk, a bath oil, a baby oil, a baby powder, a shower gel, a shower cream, a sunscreen lotion, a sunscreen cream, a suntan cream, a skin lotion, a skin cream, a UV protection cosmetic, a cleansing milk, a depilatory cosmetic, a face and body lotion, a face and body cream, a skin whitening cream, a hand lotion, a hair lotion, a cosmetic cream, jasmine oil, a bath soap, a liquid soap, a beauty soap, a shampoo, a hand cleanser (hand cleaner), a medicated soap (non-medical), a cream soap, a facial wash, a body cleanser, a scalp cleanser, a hair rinse, a cosmetic soap, a tooth whitening gel, a toothpaste, etc. To this end, the composition of the present invention may further include a solvent, an appropriate carrier, an excipient, or a diluent commonly used in the manufacture of a cosmetic composition.

[0071] In the present invention, the type of solvent that can be further added to the cosmetic composition is not particularly limited, but for example, water, saline solution, DMSO, or a combination thereof can be used. In addition, carriers, excipients, or diluents include, but are not limited to, purified water, oils, waxes, fatty acids, fatty alcohols, fatty acid esters, surfactants, humectants, thickeners, antioxidants, viscosity stabilizers, chelating agents, buffers, lower alcohols, and the like. In addition, whitening agents, moisturizers, vitamins, sunscreens, perfumes, dyes, antibiotics, antibacterial agents, and antifungal agents can be included as needed.

[0072] In addition, in the present invention, hydrogenated vegetable oil, castor oil, cottonseed oil, olive oil, palm oil, jojoba oil, and avocado oil can be used as the oil, and beeswax, spermaceti, carnauba, candelilla, montan, ceresin, liquid paraffin, and lanolin can be used as the wax.

[0073] In addition, in the present invention, stearic acid, linoleic acid, linolenic acid, and oleic acid can be used as the fatty acid, cetyl alcohol, octyl dodecanol, oleyl alcohol, panthenol, lanolin alcohol, stearyl alcohol, and hexadecanol can be used as the fatty acid alcohol, and isopropyl myristate, isopropyl palmitate, and butyl stearate can be used as the fatty acid ester. As the surfactant, cationic surfactants, anionic surfactants, and nonionic surfactants known in the art can be used, and surfactants derived from natural products are preferable if possible. In addition, it can include a hygroscopic agent, a thickener, an antioxidant, etc. widely known in the cosmetics field, and the types and amounts thereof are as known in the art.

[0074] In one embodiment of the present invention, a pharmaceutical composition for treating or preventing fibrosis is provided, comprising a p300 inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient.

[0075] In another embodiment of the present invention, a pharmaceutical composition is provided, wherein the p300 inhibitor is a p300 histone acetyl-transferase inhibitor.

[0076] In another embodiment of the present invention, a pharmaceutical composition is provided, wherein the p300 histone acetyl-transferase inhibitor is at least one selected from the group consisting of GNE-781, SGC-CBP30, CPI-637, NEO2734, CPI-637, A-485, PF-CBP1 HCl, I-CBP112, C646, EML 425, YF-2, ICG-001, Anacardic Acid, Curcuminm, PRI-724, Nordihydroguaiaretic acid (NDGA), NEO2734, and Bronopol.

[0077] In another embodiment of the present invention, a pharmaceutical composition is provided, wherein the p300 histone acetyl-transferase inhibitor is represented by the following chemical formula 1.

[0078] [Chemical Formula 1]

[0079]

[0080] In another embodiment of the present invention, a pharmaceutical composition for treating or preventing fibrosis is provided, which comprises administering together bronopol represented by the chemical formula 1 and TGF-β.

[0081] In another embodiment of the present invention, a pharmaceutical composition is provided, wherein the fibrosis is at least one selected from the group consisting of pulmonary fibrosis, uterine fibroids, myelofibrosis, liver fibrosis, heart fibrosis, multiple sclerosis, kidney fibrosis, cystic fibrosis, neutropenia, skeletal muscle fibrosis, scleroderma, dermatomyositis, mediastinal fibrosis, and splenic fibrosis due to sickle cell anemia.

[0082] In another embodiment of the present invention, a pharmaceutical composition is provided, wherein the pulmonary fibrosis is at least one selected from the group consisting of idiopathic pulmonary fibrosis, nonspecific interstitial pneumonia, acute interstitial pneumonia, cryptogenic organizing pneumonia, respiratory bronchiolitis-associated interstitial lung, desquamative interstitial pneumonia, lymphoid interstitial pneumonia, interstitial pulmonary fibrosis, and diffuse pulmonary fibrosis.

[0083] In another embodiment of the present invention, the pharmaceutical composition is provided for oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual or rectal administration.

[0084] In one embodiment of the present invention, a food composition for improving or preventing fibrosis is provided, comprising a p300 inhibitor as an active ingredient.

[0085] In another embodiment of the present invention, a food composition is provided, wherein the p300 inhibitor is a p300 histone acetyl-transferase inhibitor.

[0086] In another embodiment of the present invention, a food composition is provided, wherein the p300 histone acetyl-transferase inhibitor is at least one selected from the group consisting of GNE-781, SGC-CBP30, CPI-637, NEO2734, CPI-637, A-485, PF-CBP1 HCl, I-CBP112, C646, EML 425, YF-2, ICG-001, Anacardic Acid, Curcuminm, PRI-724, Nordihydroguaiaretic acid (NDGA), NEO2734, and Bronopol.

[0087] In another embodiment of the present invention, a food composition is provided, wherein the p300 histone acetyl-transferase inhibitor is represented by the following chemical formula 1.

[0088] [Chemical Formula 1]

[0089]

[0090] In another embodiment of the present invention, a food composition is provided, wherein the fibrosis is at least one selected from the group consisting of pulmonary fibrosis, uterine fibroids, myelofibrosis, liver fibrosis, heart fibrosis, multiple sclerosis, kidney fibrosis, cystic fibrosis, neutropenia, skeletal muscle fibrosis, scleroderma, dermatomyositis, mediastinal fibrosis, and splenic fibrosis due to sickle cell anemia.

[0091] In another embodiment of the present invention, a food composition is provided, wherein the pulmonary fibrosis is at least one selected from the group consisting of idiopathic pulmonary fibrosis, nonspecific interstitial pneumonia, acute interstitial pneumonia, cryptogenic organizing pneumonia, respiratory bronchiolitis-associated interstitial lung, desquamative interstitial pneumonia, lymphoid interstitial pneumonia, interstitial pulmonary fibrosis, and diffuse pulmonary fibrosis.

[0092] In one embodiment of the present invention, a cosmetic composition for improving or preventing fibrosis is provided, comprising a p300 inhibitor as an active ingredient.

[0093] In another embodiment of the present invention, a cosmetic composition is provided, wherein the p300 inhibitor is a p300 histone acetyl-transferase inhibitor.

[0094] In another embodiment of the present invention, a cosmetic composition is provided, wherein the p300 histone acetyl-transferase inhibitor is at least one selected from the group consisting of GNE-781, SGC-CBP30, CPI-637, NEO2734, CPI-637, A-485, PF-CBP1 HCl, I-CBP112, C646, EML 425, YF-2, ICG-001, Anacardic Acid, Curcuminm, PRI-724, Nordihydroguaiaretic acid (NDGA), NEO2734, and Bronopol.

[0095] In another embodiment of the present invention, a cosmetic composition is provided, wherein the p300 histone acetyl-transferase inhibitor is represented by the following chemical formula 1.

[0096] [Chemical Formula 1]

[0097]

[0098] In another embodiment of the present invention, a cosmetic composition is provided wherein the fibrosis is scleroderma.

[0099] The present invention relates to innovative new drugs and next-generation biopharmaceuticals, and more particularly, to an advanced biopharmaceutical composition for treating fibrosis developed using an ICT-based new drug development platform technology. In particular, the present invention relates to a p300 inhibitor, and more particularly, to a p300 histone acetyl-transferase inhibitor. The composition of the present invention is characterized by a remarkably excellent inhibitory effect on fibrosis-related diseases that have developed or are likely to develop in a subject by inhibiting the activity of histone acetyl-transferase (HAT). Thus, the present invention can treat or prevent fibrosis by including a p300 inhibitor as an active ingredient.

[0100] Figure 1 shows the results of a p300 inhibition assay performed on 2,222 drugs from Selleckem's FDA-approved drug library (Cat No. L1300) using an assay kit (Cat No. MA-0146) from Akrivis Bio. The substance indicated by the blue arrow is Bronopol.

[0101] Figure 2 shows the IC50 experiment results of the selected p300 inhibitor, Bronopol.

[0102] Figure 3a shows the results of confirming the expression of Acta2, a fibrosis target gene induced by TGF-beta, through qRT-PCR.

[0103] Figure 3b shows the results of confirming the expression of FN, a fibrosis target gene induced by TGF-beta, through qRT-PCR.

[0104] Figure 3a shows the results of confirming the expression of Col1a1, a fibrosis target gene induced by TGF-beta, through qRT-PCR.

[0105] Figure 4a shows the results of confirming the expression of Col3a1, a fibrosis target gene induced by TGF-beta, through qRT-PCR.

[0106] Figure 4b shows the results of confirming the expression of FN, a fibrosis target gene induced by TGF-beta, through qRT-PCR.

[0107] Figure 4c shows the results of confirming the expression of CTGF, a fibrosis target gene induced by TGF-beta, through qRT-PCR.

[0108] Figure 4d shows the results of confirming the expression of Vimentin, a fibrosis target gene induced by TGF-beta, through qRT-PCR.

[0109] Hereinafter, the present invention will be described in more detail through examples. These examples are intended solely to illustrate the present invention more specifically, and it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples, in accordance with the gist of the present invention.

[0110] [Example]

[0111] Example 1: Screening for p300 inhibitors - p300 inhibition assay

[0112] A p300 inhibition assay was performed on 2222 drugs from the FDA approved drug library (Cat No. L1300) of Selleckem using an assay kit (Cat MA-0146) from Akrivis Bio.

[0113] Specifically, using histone 3 peptide as a substrate, p300 enzyme and the inhibitor to be screened were added, and the degree of inhibition of fluorescence generated by reaction with Acetyl CoA was measured. The degree of inhibition of p300 enzyme by drugs in the FDA approved drug library of Selleckem was calculated based on the control group containing only p300 enzyme as 100%. C646 (commercial p300 selective inhibitor) was used as a positive control to calculate the degree of p300 inhibition, and 1 uM of library drugs was used.

[0114] As a result, as shown in Figure 1, about 20 drugs that inhibit p300 by more than 60% compared to the positive control group, C646, were screened.

[0115] Example 2: IC50 test of selected p300 inhibitor (Bronopol)

[0116] Among the approximately 20 candidate substances selected in Example 1 above, Bronopol, a substance previously used only as an antibacterial agent or preservative and not known as a p300 inhibitor, was selected and an IC50 experiment was conducted.

[0117] Specifically, the assay kit from Akrivis Bio. (Cat MA-0146) was used to react with serial concentrations of inhibitors (5 uM, 1 uM, 500 nM, 100 nM, etc.), and the IC50 concentration was calculated using Graphpad Prism software.

[0118] As a result, as shown in Figure 2, the IC50 concentration of C646, which is a positive control, is approximately 400 nM, while the IC50 concentration of Bronopol is 80 nM, which is a much lower concentration, and thus it showed a more excellent inhibitory effect on p300 than the positive control.

[0119] Example 3: Confirmation of decreased expression of fibrosis-related genes in a lung fibrosis cell model.

[0120] Mouse fibroblast (Mlg) cells, a lung fibroblast cell line, were plated in 60 mm dishes. The next day, 2 uM C646 or Bronopol was treated in serum-starved medium, and 20 ng / ml of TGF-beta was added 2 hours later to induce the expression of fibrosis target genes. Cells were harvested after 24 hours, and qRT-PCR was performed using primers for the indicated fibrosis-related genes.

[0121] As a result, as shown in Figures 3a to 3c, it was confirmed that fibrosis-related genes (Acta2, FN, Col1a1) increased by TGF-beta were significantly reduced by Bronopol, which was selected as a p300 inhibitor. This confirmed that Bronopol, which was selected as a p300 inhibitor, can prevent or treat fibrosis by suppressing the expression of fibrosis-related genes in a lung fibrosis cell model.

[0122] Example 4: Confirmation of decreased expression of fibrosis-related genes in a kidney fibrosis cell model.

[0123] HK2 cells, a renal proximal tubule cell line, were plated in 60 mm dishes, and the next day, 5 uM of C646 or Bronopol was treated in serum-starved medium. After 2 hours, 20 ng / ml of TGF-beta was added to induce the expression of fibrosis target genes. Cells were harvested after 24 hours, and qRT-PCR was performed using primers for the indicated fibrosis-related genes.

[0124] As a result, as shown in Figures 4a to 4d, it was confirmed that fibrosis-related genes (Col3a1, FN, CTGF, Vimentin) increased by TGF-beta were significantly reduced by Bronopol, which was selected as a p300 inhibitor. This confirmed that Bronopol, which was selected as a p300 inhibitor, can prevent or treat fibrosis by suppressing the expression of fibrosis-related genes in a renal fibrosis cell model.

[0125] While specific aspects of the present invention have been described in detail above, it should be apparent to those skilled in the art that these specific descriptions are merely preferred embodiments and do not limit the scope of the present invention. Therefore, the substantial scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A pharmaceutical composition for treating or preventing fibrosis, comprising a p300 inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient.

2. In paragraph 1, A pharmaceutical composition wherein the above p300 inhibitor is a p300 histone acetyl-transferase inhibitor.

3. In paragraph 2, A pharmaceutical composition, wherein the p300 histone acetyl-transferase inhibitor is at least one selected from the group consisting of GNE-781, SGC-CBP30, CPI-637, NEO2734, CPI-637, A-485, PF-CBP1 HCl, I-CBP112, C646, EML 425, YF-2, ICG-001, Anacardic Acid, Curcuminm, PRI-724, Nordihydroguaiaretic acid (NDGA), NEO2734, and Bronopol.

4. In paragraph 3, The above p300 histone acetyl-transferase inhibitor is a pharmaceutical composition represented by the following chemical formula 1: [Chemical Formula 1] 5. In paragraph 4, A pharmaceutical composition, wherein the fibrosis is at least one selected from the group consisting of pulmonary fibrosis, uterine fibroids, myelofibrosis, liver fibrosis, heart fibrosis, multiple sclerosis, kidney fibrosis, cystic fibrosis, neutropenia, skeletal muscle fibrosis, scleroderma, dermatomyositis, mediastinal fibrosis, and splenic fibrosis due to sickle cell anemia.

6. In paragraph 5, A pharmaceutical composition, wherein the pulmonary fibrosis is at least one selected from the group consisting of idiopathic pulmonary fibrosis, nonspecific interstitial pneumonia, acute interstitial pneumonia, cryptogenic organizing pneumonia, respiratory bronchiolitis-associated interstitial lung, desquamative interstitial pneumonia, lymphoid interstitial pneumonia, interstitial pulmonary fibrosis, and diffuse pulmonary fibrosis.

7. In paragraph 6, The pharmaceutical composition is for oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual or rectal administration.

8. A food composition for improving or preventing fibrosis, comprising a p300 inhibitor as an active ingredient.

9. In paragraph 8, A food composition wherein the above p300 inhibitor is a p300 histone acetyl-transferase inhibitor.

10. In paragraph 9, A food composition, wherein the above p300 histone acetyl-transferase inhibitor is at least one selected from the group consisting of GNE-781, SGC-CBP30, CPI-637, NEO2734, CPI-637, A-485, PF-CBP1 HCl, I-CBP112, C646, EML 425, YF-2, ICG-001, Anacardic Acid, Curcuminm, PRI-724, Nordihydroguaiaretic acid (NDGA), NEO2734, and Bronopol.

11. In paragraph 10, The above p300 histone acetyl-transferase inhibitor is a food composition represented by the following chemical formula 1: [Chemical Formula 1] 12. In paragraph 11, A food composition, wherein the fibrosis is at least one selected from the group consisting of pulmonary fibrosis, uterine fibroids, myelofibrosis, liver fibrosis, heart fibrosis, multiple sclerosis, kidney fibrosis, cystic fibrosis, neutropenia, skeletal muscle fibrosis, scleroderma, dermatomyositis, mediastinal fibrosis, and splenic fibrosis due to sickle cell anemia.

13. In paragraph 12, A food composition, wherein the pulmonary fibrosis is at least one selected from the group consisting of idiopathic pulmonary fibrosis, nonspecific interstitial pneumonia, acute interstitial pneumonia, cryptogenic organizing pneumonia, respiratory bronchiolitis-associated interstitial lung, desquamative interstitial pneumonia, lymphoid interstitial pneumonia, interstitial pulmonary fibrosis, and diffuse pulmonary fibrosis.

14. A cosmetic composition for improving or preventing fibrosis, comprising a p300 inhibitor as an active ingredient.

15. In paragraph 14, A cosmetic composition wherein the above p300 inhibitor is a p300 histone acetyl-transferase inhibitor.

16. In paragraph 15, A cosmetic composition, wherein the p300 histone acetyl-transferase inhibitor is at least one selected from the group consisting of GNE-781, SGC-CBP30, CPI-637, NEO2734, CPI-637, A-485, PF-CBP1 HCl, I-CBP112, C646, EML 425, YF-2, ICG-001, Anacardic Acid, Curcuminm, PRI-724, Nordihydroguaiaretic acid (NDGA), NEO2734, and Bronopol.

17. In paragraph 16, The above p300 histone acetyl-transferase inhibitor is a cosmetic composition represented by the following chemical formula 1: [Chemical Formula 1] 18. In paragraph 17, A cosmetic composition wherein the above fibrosis is scleroderma.

19. A method for preventing or treating fibrosis, comprising the step of administering a p300 inhibitor or a pharmaceutically acceptable salt thereof to a subject.

20. In paragraph 19, A method for preventing or treating fibrosis, wherein the above p300 inhibitor is a p300 histone acetyl-transferase inhibitor.

21. In paragraph 20, A method for preventing or treating fibrosis, wherein the p300 histone acetyl-transferase inhibitor is at least one selected from the group consisting of GNE-781, SGC-CBP30, CPI-637, NEO2734, CPI-637, A-485, PF-CBP1 HCl, I-CBP112, C646, EML 425, YF-2, ICG-001, Anacardic Acid, Curcuminm, PRI-724, Nordihydroguaiaretic acid (NDGA), NEO2734, and Bronopol.

22. In paragraph 21, The above p300 histone acetyl-transferase inhibitor is represented by the following chemical formula 1, and is a method for preventing or treating fibrosis: [Chemical Formula 1]

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