Agent for treating or preventing idiopathic pulmonary fibrosis

Abstract

To provide an agent for treating or preventing idiopathic pulmonary fibrosis.SOLUTION: An agent for treating or preventing idiopathic pulmonary fibrosis (IPF) is provided, the agent containing an ABL inhibitor, an RET inhibitor, an SRC family inhibitor, an ERK1 / 2 phosphorylation inhibitor, or an FLT3 inhibitor.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present disclosure relates to a therapeutic or preventive agent for idiopathic pulmonary fibrosis, a method for treating or preventing a patient suffering from or at risk of suffering from idiopathic pulmonary fibrosis using the same, and a marker or diagnostic agent for idiopathic pulmonary fibrosis. More specifically, the present disclosure relates to a technology for constructing a molecular network related to a disease based on medical information and using the molecular network to find a therapeutic or diagnostic agent of interest. [Background technology]

[0002] It is known that the current drug discovery has a high failure rate in obtaining proof of concept (POC) in phase 2 clinical trials. Idiopathic pulmonary fibrosis is a serious disease, but highly effective drugs have not yet been provided. Summary of the Invention [Means for solving the problem]

[0003] In the present disclosure, by using medical information of patients with the target disease for drug discovery target discovery and omics data linked to the medical information, drug discovery targets are discovered by stratifying patients, and based on the results, therapeutic agents and markers thereof for the target disease such as idiopathic pulmonary fibrosis are provided.

[0004] Thus, the present disclosure provides: (Item 1) An agent for treating or preventing idiopathic pulmonary fibrosis (IPF), comprising an ABL inhibitor, a RET inhibitor, an SRC family inhibitor, an ERK1 / 2 phosphorylation inhibitor, or an FLT3 inhibitor. (Item 2) The therapeutic or prophylactic agent according to the above item, which has a function as an inhibitor of at least two or more of an ABL inhibitor, a RET inhibitor, an SRC family inhibitor, an ERK1 / 2 phosphorylation inhibitor, and an FLT3 inhibitor. (Item 3) The therapeutic or prophylactic agent according to any one of the preceding items, wherein the therapeutic or prophylactic agent functions as an ABL inhibitor, a RET inhibitor, an SRC family inhibitor, an ERK1 / 2 phosphorylation inhibitor, and an FLT3 inhibitor. (Item 4) A therapeutic or prophylactic agent according to any one of the preceding items, comprising ponatinib. (Item a1) A composition comprising an ABL inhibitor, a RET inhibitor, an SRC family inhibitor, an ERK1 / 2 phosphorylation inhibitor, or an FLT3 inhibitor for treating or preventing idiopathic pulmonary fibrosis (IPF). (item a2) The composition according to any one of the preceding items, comprising a drug having inhibitory functions of at least two or more of an ABL inhibitor, a RET inhibitor, an SRC family inhibitor, an ERK1 / 2 phosphorylation inhibitor, and an FLT3 inhibitor. (Item a3) The composition according to any one of the preceding items, wherein the composition comprises a drug that functions as an ABL inhibitor, a RET inhibitor, an SRC family inhibitor, an ERK1 / 2 phosphorylation inhibitor, and an FLT3 inhibitor. (item a4) The composition of any one of the preceding items, comprising ponatinib. (Item b1) A method for treating or preventing a patient suffering from or at risk of suffering from idiopathic pulmonary fibrosis, the method comprising administering to the subject a therapeutically or prophylactically effective amount of an ABL inhibitor, a RET inhibitor, an SRC family inhibitor, an ERK1 / 2 phosphorylation inhibitor, or an FLT3 inhibitor. (Item b2) The method according to any one of the above items, wherein the administration step comprises administering a drug having inhibitory functions of at least two or more of an ABL inhibitor, a RET inhibitor, an SRC family inhibitor, an ERK1 / 2 phosphorylation inhibitor, and an FLT3 inhibitor. (Item b3) The method according to any one of the above items, wherein the administering step comprises administering a drug having the functions of an ABL inhibitor, a RET inhibitor, an SRC family inhibitor, an ERK1 / 2 phosphorylation inhibitor, and an FLT3 inhibitor. (Item b4) The method according to any one of the preceding claims, wherein the administering step comprises administering ponatinib. (Item A1) A marker or diagnostic agent for idiopathic pulmonary fibrosis (IPF), comprising a hub molecule in a network composed of molecules related to one or more clinical information of idiopathic pulmonary fibrosis (IPF), or a detection agent thereof. (Item A2) The marker or diagnostic agent according to any one of the preceding items, wherein the molecule is one or more molecules selected from the group consisting of ANXA7, ITIH1, ITIH2, ITIH3, ITIH4, ITIH5, ITIH6, MRPS17, AGN, SRI, ALOX12, PEF1, PNP, FHL1, PCMT1, PIP4P2, HEBP2, CAPN1, PLXDC2, PTPN6, LYN, TAOK3, RAN, CNP, and MIF. (Item A3) The marker or diagnostic agent of any one of the preceding items, wherein the molecule is selected from the group consisting of ANXA7, ITIH1, ITIH2, ITIH3, ITIH4, ITIH5, ITIH6, MRPS17, SRI, ALOX12, PEF1, PTPN6, LYN, RAN, and MIF. (Item A4) The marker or diagnostic agent according to any one of the preceding items, wherein the molecule is selected from the group consisting of LYN, PTPN6, MIF, and RAN. (Item A5) A marker or diagnostic agent according to any one of the above items, comprising a molecule associated with multiple clinical information of idiopathic pulmonary fibrosis (IPF), or a detection agent thereof. (Item A6) The marker or diagnostic agent according to any one of the preceding items, wherein the molecule is one or more molecules selected from the group consisting of ANXA7, ITIH1, ITIH2, ITIH3, ITIH4, ITIH5, ITIH6, MRPS17, AGN, SRI, ALOX12, and PEF1. (Item A7) The marker or diagnostic agent according to any one of the preceding items, wherein the medical information includes image findings, medical records, and / or blood test values ​​characteristic of IPF. (Item A8) A marker or diagnostic agent for idiopathic pulmonary fibrosis (IPF), comprising a molecule that controls the expression of molecules related to multiple clinical information of idiopathic pulmonary fibrosis (IPF), or a detection agent thereof. (Item A9) The marker or diagnostic agent according to any one of the preceding items, wherein the molecule is one or more molecules selected from the group consisting of ESR1, CCDN1, NOS2, CCR2, PRKAA1, MKNK1, and MMP14. (Item B1) A therapeutic or preventive agent for idiopathic pulmonary fibrosis (IPF), comprising a regulator or inhibitor of a hub molecule in a network composed of molecules related to one or more clinical information of IPF. (Item B2) The therapeutic or prophylactic agent according to any one of the above items, wherein the molecule is one or more molecules selected from the group consisting of ANXA7, ITIH1, ITIH2, ITIH3, ITIH4, ITIH5, ITIH6, MRPS17, AGN, SRI, ALOX12, PEF1, PNP, FHL1, PCMT1, PIP4P2, HEBP2, CAPN1, PLXDC2, PTPN6, LYN, TAOK3, RAN, CNP, and MIF. (Item B3) The therapeutic or prophylactic agent according to any one of the above items, wherein the molecule is selected from the group consisting of ANXA7, ITIH1, ITIH2, ITIH3, ITIH4, ITIH5, ITIH6, MRPS17, SRI, ALOX12, PEF1, PTPN6, LYN, RAN, and MIF. (Item B4) The therapeutic or prophylactic agent according to any one of the preceding items, wherein the molecule is selected from the group consisting of LYN, PTPN6, MIF, and RAN. (Item B5) The therapeutic or prophylactic agent according to any one of the above items, comprising a regulator or inhibitor of a molecule related to multiple clinical information of idiopathic pulmonary fibrosis (IPF). (Item B6) The therapeutic or prophylactic agent according to any one of the above items, wherein the molecule is one or more molecules selected from the group consisting of ANXA7, ITIH1, ITIH2, ITIH3, ITIH4, ITIH5, ITIH6, MRPS17, AGN, SRI, ALOX12, and PEF1. (Item B7) The therapeutic or preventive agent according to any one of the above items, wherein the medical information includes image findings, medical records, and / or blood test values ​​characteristic of IPF. (Item B8) The therapeutic or prophylactic agent according to any one of the above items, wherein the regulator or inhibitor comprises a compound or drug described in the right column of the table below. [Table 1A] [Table 1B] (Item C1) A screening method for discovering a therapeutic or preventive agent for a certain disease, comprising: Identifying molecules that have a regulatory effect on specific networks associated with the disease; determining whether said molecule functions as a therapeutic or prophylactic agent for said disease; A method comprising: (Item C2) The method according to any one of the above items, wherein the network is constructed based on one or more medical information of the disease. (Item C3) The method according to any one of the preceding items, wherein the medical information includes characteristic image findings, medical records, and / or blood test values ​​of the disease. (Item C4) The step of confirming comprises: (a) collecting information on the molecule using existing databases and / or literature information and confirming its relationship with the disease; (b) confirming the expression of the molecule in fibrotic tissue; (c) searching for information on compounds related to the regulation of the molecule using existing databases and / or literature information; (d) reproducing the fibrosis phenomenon at the cellular level and confirming the action of the molecule; and / or (e) identifying a network formed by the molecules and determining whether the network shows an abnormality in the disease; The method according to any one of the preceding items, wherein the method is carried out by any one or more of the following: (Item C5) The method of any one of the preceding claims, wherein the disease comprises idiopathic pulmonary fibrosis (IPF).

[0005] It is contemplated that one or more of the above features may be provided in combinations other than those specifically described herein.Further embodiments and advantages of the present disclosure will be recognized by those skilled in the art upon reading and understanding the following detailed description, if necessary.

[0006] Furthermore, features and notable actions and effects of the present disclosure other than those described above will become apparent to those skilled in the art by referring to the following description of the preferred embodiments of the present invention and the drawings. Effect of the Invention

[0007] This disclosure enables data-driven drug discovery target discovery using human data, providing promising drug targets for intractable diseases such as idiopathic pulmonary fibrosis, whose disease onset mechanisms are not fully understood at the molecular level. [Brief description of the drawings]

[0008] [Figure 1A] FIG. 1A is a flow chart of medical information and serum sample collection in one embodiment of the present disclosure. [Figure 1B] FIG. 1B is a schematic diagram showing a structuring process of medical information in one embodiment of the present disclosure. [Figure 2A] FIG. 2A is a cohort data structure diagram according to one embodiment of the present disclosure. [Figure 2B] FIG. 2B is a conceptual diagram of an analysis workflow according to an embodiment of the present disclosure. [Figure 2C] FIG. 2C is a conceptual diagram of subset binding according to an embodiment of the present disclosure. [Diagram 3] FIG. 3 is a schematic diagram showing protein-protein interactions (PPIs) and hub molecules by TargetMine of proteins found by analysis in one embodiment of the present disclosure. [Figure 4] 4 is a schematic diagram showing a network formed by IPA core molecules in one embodiment of the present disclosure. We found a network in which all seven core molecules were mounted (Carbohydrate Metabolism, Small Molecule Biochemistry, Cellular Assembly and Organization). [Diagram 5] FIG. 5 is a schematic diagram showing a regulatory relationship network of ponatinib based on an analysis of upstream regulatory factors of a core molecule in one embodiment of the present disclosure. [Figure 6] FIG. 6 is a photograph showing the results of confirming the expression of major proteins in lesions (immunostaining, independent cohort) in one embodiment of the present disclosure. [Figure 7A] FIG. 7A is a graph showing the EMT inhibitory effect of SB431542. [Figure 7B] FIG. 7B is a graph showing the EMT inhibitory effect of ponatinib. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] The present disclosure will be described below while showing the best mode. Throughout this specification, the expression of the singular form should be understood to include the concept of the plural form, unless otherwise specified. Therefore, the singular article (for example, in the case of English, "a", "an", "the", etc.) should be understood to include the concept of the plural form, unless otherwise specified. In addition, it should be understood that the terms used in this specification are used in the sense commonly used in the field, unless otherwise specified. Therefore, unless otherwise defined, all technical terms and scientific and technical terms used in this specification have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. In case of conflict, the present specification (including definitions) will take precedence.

[0010] The following provides definitions of terms particularly used in this specification and / or explains basic technical content as appropriate.

[0011] As used herein, "about" means ±10% of the preceding numerical value.

[0012] As used herein, "ABL" refers to the abelson (abl) gene or its gene product. The tyrosine protein kinase ABL1, known as ABL1, is a protein that is encoded by the ABL1 gene on chromosome 9 in humans and is said to be involved in the processes of cell differentiation, cell division, cell adhesion and / or stress response. c-Abl refers to the gene found in mammalian genomes, and v-Abl refers to the viral gene originally isolated from the Abelson murine leukemia virus.

[0013] As used herein, the term "ABL inhibitor" refers to an agent that reduces or eliminates the function of ABL by inhibiting the function, expression, or production of Abl, etc. Examples of ABL inhibitors include, but are not limited to, ponatinib, temozolomide, imatinib, sunitinib, nilotinib, saracatinib, umbralisib, and bosutinib.

[0014] As used herein, "RET" refers to a receptor tyrosine kinase that binds extracellular signaling molecules of the GDNF family and is encoded in humans by the RET gene. Loss-of-function mutations in the RET gene are associated with the development of Hirschsprung's disease, while gain-of-function mutations are associated with the development of various types of cancer, including medullary thyroid carcinoma and multiple endocrine neoplasia types 2A and 2B. Mutations in RET have been shown to induce dysregulation of genes encoding inflammatory mediators that regulate thyroid cell function, such as chemokine receptors, cytokines, and metalloproteases.

[0015] In this specification, the term "RET inhibitor" refers to an agent that reduces or eliminates the function of RET by inhibiting the function, expression, or production of RET. Examples of RET inhibitors include, but are not limited to, ponatinib, imatinib, sorafenib, sunitinib, cabozantinib, crizotinib, motesanib, pazopanib, alectinib, pralsetinib, selpercatinib, lenvatinib, and vandetanib.

[0016] As used herein, "SRC" (proto-oncogene tyrosine-protein kinase Src) is a non-receptor tyrosine kinase protein encoded by the SRC gene in humans. It is also known as the proto-oncogene c-Src or simply c-Src. This protein phosphorylates specific tyrosine residues in other proteins. Increased activity of c-Src tyrosine kinase has been suggested to be associated with cancer progression by promoting other signals. c-Src contains SH2 domains, SH3 domains, and tyrosine kinase domains. There are nine Src family kinases: c-Src, YES1, FYN, FGR, LYN, BLK, HCK, and Lck. The expression of these Src family members is not uniform across all tissues and cell types. Src, Fyn, and Yes are ubiquitously expressed in all cell types, while the others are commonly found in hematopoietic cells. Src family kinases are important intracellular signaling proteins involved in acute inflammatory responses, and their phosphorylation is one of the factors that determine the degree of expression and production of inflammatory mediators.

[0017] As used herein, the term "SRC family inhibitor" refers to an agent that reduces or eliminates the function of Src family kinase by inhibiting the function, expression, or production of Src family kinase. Examples of SRC family inhibitors include, but are not limited to, ponatinib, afatinib, dasatinib, saracatinib, bosutinib, vandetanib, nilotinib, and erlotinib.

[0018] In this specification, "ERK1 / 2" refers to one of the MAPK (mitogen-activated protein kinase) subfamily, consisting of ERK1 with a molecular weight of 44 kDa and ERK2 with a molecular weight of 42 kDa. The primary amino acid sequences of these two kinases share 85% homology with each other. ERK1 / 2 transmit signals from cell surface receptors to nuclear transcription factors and regulate various cellular processes. ERK1 / 2 is also known to be stimulated by cytokines, growth factors, irradiation, osmotic pressure and temperature fluctuations, physical stress, etc. Activation of ERK1 and ERK2 occurs by double phosphorylation of the TEY motif at the human Thr202 / Tyr204 sequence or the rat and mouse Thr183 / Tyr185 sequence of the upstream MAP kinases MEK1 and MEK2. Activated MAP kinases translocate to the nucleus, where they phosphorylate transcription factors that regulate cell proliferation, apoptosis, differentiation, etc.

[0019] As used herein, the term "ERK1 / 2 phosphorylation inhibitor" refers to an agent that reduces or eliminates the function of ERK1 / 2 by inhibiting the function, expression, or production of ERK1 / 2. Examples of ERK1 / 2 inhibitors include, but are not limited to, ponatinib, vemurafenib, daberafenib, selumetinib, encorafenib, and binimetinib.

[0020] As used herein, "FLT3" refers to a protein encoded by the FLT3 gene in humans, also known as CD135 or fetal liver kinase-2 (Flk2). FLT3 is a cytokine receptor belonging to receptor tyrosine kinase class III. It is expressed on the surface of many hematopoietic progenitor cells, and FLT3 signal transduction is important for the normal development of hematopoietic stem cells and progenitor cells. The FLT3 gene is one of the most frequently mutated genes in acute myeloid leukemia (AML), and it has been reported that wild-type FLT3 is present at high levels in blast cells of some AML patients without FLT3 mutations. These high levels may be associated with poor prognosis.

[0021] As used herein, the term "FLT3 inhibitor" refers to an agent that reduces or eliminates the function of FLT3 by inhibiting the function, expression, or production of FLT3. Examples of FLT3 inhibitors include ponatinib, nintedanib, regorafenib, sunitinib, midostaurin, zotiraciclib, sorafenib, cabozantinib, crizotinib, imatinib, quizartinib, Examples of such agents include, but are not limited to, famitinib, crenolanib, pralsetinib, gilteritinib, dovitinib, brigatinib, fedratinib, pexidartinib, amuvatinib, and lestaurtinib.

[0022] In the present disclosure, with respect to ABL inhibitors, RET inhibitors, SRC family inhibitors, ERK1 / 2 phosphorylation inhibitors, and FLT3 inhibitors, it is understood that while a substance may have only one inhibitory effect of each, the same substance may have two or more inhibitory effects.

[0023] In this specification, the term "medical information" is broadly interpreted to mean any information that a medical professional has come to know about a patient's physical condition, medical condition, treatment, etc. in the course of medical care. For example, it includes image findings characteristic of a disease, medical examination records, and / or blood test results.

[0024] As used herein, the term "molecule associated with medical information" refers to a molecule whose function, expression, production, etc. changes in response to changes in medical information.

[0025] As used herein, the term "hub molecule" refers to a molecule that has many interactions with other molecules in a network constructed by a plurality of molecules. Typically, a hub molecule refers to a molecule that, compared to other molecules, regulates the network more when the hub molecule is regulated than when the other molecules are regulated.

[0026] As used herein, "treatment" refers broadly to either preventive and / or therapeutic, and in the narrow sense includes alleviating, attenuating, or improving at least one symptom of a disease or condition, preventing additional symptoms, inhibiting a disease or condition, for example, suppressing the onset of a disease or condition, relieving a disease or condition, causing regression of a disease or condition, alleviating a condition caused by a disease or condition, or arresting a symptom of a disease or condition, for the purpose of improving (curing) a pathological condition. As used herein, "treatment" refers to alleviating, attenuating, or improving at least one symptom of a disease or condition, for the purpose of improving (curing) a pathological condition.

[0027] As used herein, "prevention" refers to preventing the development of clinical symptoms of a disease state in a subject who may be exposed to or susceptible to the disease state, but who has not yet experienced or exhibited symptoms of the disease state.

[0028] In this specification, the term "gene" refers to a factor that determines a genetic trait, and "gene" may be a nucleic acid itself, may refer to "polynucleotide," "oligonucleotide," "RNA," and "DNA," and may sometimes refer to a protein, polypeptide, oligopeptide, or peptide encoded by a nucleic acid, and those skilled in the art can appropriately understand it depending on the context. Such a gene encoding a protein may be endogenous or exogenous to the target organism. In addition, these known genes can be used appropriately. Genes can be used regardless of origin. That is, genes may be derived from organisms of other species or genus other than the target organism, or may be derived from organisms such as animals, plants, fungi (molds, etc.), and bacteria. Information on such genes can be appropriately obtained by those skilled in the art by accessing websites such as NCBI (National Center for Biotechnology Information; http: / / www.ncbi.nlm.nih.gov). These genes may be genes encoding proteins that have a certain relationship with sequence information disclosed in databases, etc., so long as they have each activity.

[0029] As used herein, "protein," "polypeptide," "oligopeptide," and "peptide" are used interchangeably herein to refer to a polymer of amino acids of any length. The polymer may be linear, branched, or cyclic. The amino acids may be natural, non-natural, or modified. The term may also include those assembled into a complex of multiple polypeptide chains. The term also includes naturally or artificially modified amino acid polymers. Such modifications include, for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification (e.g., conjugation with a labeling moiety). The definition also includes, for example, polypeptides containing one or more analogs of amino acids (e.g., including non-natural amino acids), peptide-like compounds (e.g., peptoids), and other modifications known in the art. As used herein, "amino acid" is a collective term for an organic compound having an amino group and a carboxyl group. When an antibody according to an embodiment of the present disclosure includes a "specific amino acid sequence," any amino acid in the amino acid sequence may be chemically modified. Any of the amino acids in the amino acid sequence may form a salt or a solvate. Any of the amino acids in the amino acid sequence may be L-type or D-type. In such cases, the protein according to the embodiment of the present disclosure may contain the above-mentioned "specific amino acid sequence". Examples of chemical modifications that amino acids contained in proteins undergo in vivo include N-terminal modifications (e.g., acetylation, myristoylation, etc.), C-terminal modifications (e.g., amidation, glycosylphosphatidylinositol addition, etc.), and side chain modifications (e.g., phosphorylation, sugar chain addition, etc.). The amino acids may be natural or unnatural as long as they satisfy the purpose of the present disclosure.

[0030] As used herein, "polynucleotide", "oligonucleotide" and "nucleic acid" are used interchangeably and refer to any length of nucleotide polymer, including DNA and RNA. This term also includes "oligonucleotide derivative" or "polynucleotide derivative". "Oligonucleotide derivative" or "polynucleotide derivative" refers to an oligonucleotide or polynucleotide that contains a derivative of nucleotide or has a different bond between nucleotides than usual, and are used interchangeably. Specific examples of such oligonucleotides include 2'-O-methyl-ribonucleotides, oligonucleotide derivatives in which the phosphodiester bond in an oligonucleotide has been converted to a phosphorothioate bond, oligonucleotide derivatives in which the phosphodiester bond in an oligonucleotide has been converted to an N3'-P5' phosphoramidate bond, oligonucleotide derivatives in which the ribose and phosphodiester bond in an oligonucleotide have been converted to a peptide nucleic acid bond, oligonucleotide derivatives in which the uracil in an oligonucleotide has been replaced with C-5 propynyl uracil, oligonucleotide derivatives in which the uracil in an oligonucleotide has been replaced with C-5 thiazole uracil, oligonucleotide derivatives in which the cytosine in an oligonucleotide has been replaced with C-5 propynyl cytosine, oligonucleotide derivatives in which the cytosine in an oligonucleotide has been replaced with phenoxazine-modified cytosine, oligonucleotide derivatives in which the ribose in DNA has been replaced with 2'-O-propyl ribose, and oligonucleotide derivatives in which the ribose in an oligonucleotide has been replaced with 2'-methoxyethoxy ribose. Unless otherwise indicated, a particular nucleic acid sequence is also intended to encompass conservatively modified variants thereof (e.g., degenerate codon substitutions) and complementary sequences, as well as the sequence explicitly indicated.Specifically, degenerate codon substitutions can be achieved by creating sequences in which the third position of one or more selected (or all) codons is substituted with mixed-base and / or deoxyinosine residues (Batzer et al., Nucleic Acid Res. 19:5081 (1991); Ohtsuka et al., J. Biol. Chem. 260: 2605-2608 (1985); Rossolini et al., Mol. Cell. Probes 8:91-98 (1994)). As used herein, "nucleic acid" is also used interchangeably with gene, cDNA, mRNA, oligonucleotide, and polynucleotide. As used herein, "nucleotide" may be natural or non-natural.

[0031] Amino acids may be referred to herein by either their commonly known three letter symbols or the one letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Nucleotides may also be referred to by their commonly accepted one letter codes. In this specification, the comparison of similarity, identity and homology of amino acid and base sequences is calculated using the sequence analysis tool BLAST with default parameters. Identity searches can be performed, for example, using NCBI's BLAST2.2.28 (published 2013.4.2). The identity value in this specification usually refers to the value when aligned under default conditions using the above BLAST. However, if a higher value is obtained by changing the parameters, the highest value is taken as the identity value. When identity is evaluated in multiple regions, the highest value among them is taken as the identity value. Similarity is a value that takes into account similar amino acids in addition to identity.

[0032] (Preferred embodiment) Preferred embodiments of the present disclosure are described below. The embodiments provided below are provided for a better understanding of the present disclosure, and the scope of the present disclosure should not be limited to the following description. Therefore, it is clear that a person skilled in the art can make appropriate modifications within the scope of the present disclosure in light of the description in this specification. In addition, the following embodiments of the present disclosure can be used alone or in combination.

[0033] (Preventive or therapeutic agent) In one aspect of the present disclosure, there is provided an agent for treating or preventing idiopathic pulmonary fibrosis (IPF), comprising an ABL inhibitor, a RET inhibitor, an SRC family inhibitor, an ERK1 / 2 phosphorylation inhibitor, or an FLT3 inhibitor.

[0034] Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, intractable respiratory disease, and is included in the idiopathic interstitial pneumonias (IIPs), which are designated as intractable diseases. IPF has a very poor prognosis, with an average survival time of 3-5 years after diagnosis and within 2 months after acute exacerbation. In many cases, the disease does not respond to steroids, and the only options for drug treatment are the anti-fibrotic drugs pirfenidone and nintedanib, which have limited therapeutic effects, and no fundamental treatment has been established. Because the pathogenic mechanism of this disease is unknown, an innovative approach to drug discovery targets that does not rely on conventional methods is required.

[0035] Exosomes are extracellular vesicles with a diameter of 30 nm to 100 nm secreted by most cells. It has been found that lipids, proteins, miRNAs, metabolic substances, etc. contained in exosomes are transferred to other cells, and are responsible for various intercellular signaling. It has become clear that the expression state of these molecules is deeply related to the state of cells and the progression of diseases in many diseases including cancer. With these discoveries, attention has been focused on the search for biomarkers using exosomes and their application to drug discovery. The present inventors have identified biomarkers that correlate with pathology and severity from proteomic analysis of exosomes in respiratory diseases including COPD. In addition, it has been suggested that miRNAs contained in serum exosomes reflect specific changes in miRNA expression in lung tissue of IPF patients with IPF. Therefore, analysis of exosomes in the serum of patients with idiopathic interstitial pneumonia, including IPF, which involves various cells and shows diverse pathologies, is likely to reflect the diverse pathologies, and we have worked to obtain comprehensive molecular information using proteomic analysis technology, which has been developing remarkably in recent years. Based on the above background, the inventors constructed a database of clinical information and serum exosome proteome data for interstitial pneumonia, including IPF, and developed a patient stratification algorithm.

[0036] In one embodiment of the present disclosure, the therapeutic or preventive agent for idiopathic pulmonary fibrosis (IPF) of the present disclosure may be an ABL inhibitor, a RET inhibitor, an SRC family inhibitor, an ERK1 / 2 phosphorylation inhibitor, or an FLT3 inhibitor, or may be an agent having the function of at least two of these inhibitors. The therapeutic or preventive agent for idiopathic pulmonary fibrosis (IPF) of the present disclosure includes the function of an ABL inhibitor, a RET inhibitor, an SRC family inhibitor, an ERK1 / 2 phosphorylation inhibitor, or an FLT3 inhibitor, and preferably the therapeutic or preventive agent has the function of at least two or more inhibitors among an ABL inhibitor, a RET inhibitor, an SRC family inhibitor, an ERK1 / 2 phosphorylation inhibitor, and an FLT3 inhibitor, and more preferably the therapeutic or preventive agent has the function of an ABL inhibitor, a RET inhibitor, an SRC family inhibitor, an ERK1 / 2 phosphorylation inhibitor, and an FLT3 inhibitor.

[0037] In one embodiment, an ABL inhibitor refers to an agent that reduces or eliminates the function of ABL by inhibiting the function, expression, or production of Abl, and examples of ABL inhibitors include, but are not limited to, ponatinib, temozolomide, imatinib, sunitinib, nilotinib, saracatinib, umbralisib, and bosutinib.

[0038] In one embodiment, a RET inhibitor refers to an agent that reduces or eliminates the function of RET by inhibiting the function, expression, or production of RET, and examples of such inhibitors include, but are not limited to, ponatinib, imatinib, sorafenib, sunitinib, cabozantinib, crizotinib, motesanib, pazopanib, alectinib, pralsetinib, selpercatinib, lenvatinib, and vandetanib.

[0039] In one embodiment, an SRC family inhibitor refers to an agent that reduces or eliminates the function of an Src family kinase by inhibiting the function, expression, or production of an Src family kinase, and examples of such inhibitors include, but are not limited to, ponatinib, afatinib, dasatinib, saracatinib, bosutinib, vandetanib, nilotinib, and erlotinib.

[0040] In one embodiment, an ERK1 / 2 phosphorylation inhibitor refers to an agent that reduces or eliminates the function of ERK1 / 2 by inhibiting the function, expression, or production of ERK1 / 2, and examples of such agents include, but are not limited to, ponatinib, vemurafenib, daberafenib, selumetinib, encorafenib, and binimetinib.

[0041] In one embodiment, the FLT3 inhibitor refers to an agent that reduces or eliminates the function of FLT3 by inhibiting the function, expression, or production of FLT3, and examples of such agents include ponatinib, nintedanib, regorafenib, sunitinib, midostaurin, zotiraciclib, sorafenib, cabozantinib, crizotinib, and imatinib. matinib, quizartinib, famitinib, crenolanib, pralsetinib, gilteritinib, dovitinib, brigatinib, fedratinib, pexidartinib, amuvatinib, lestaurtinib, and the like can be mentioned, but are not limited to these.

[0042] In the present disclosure, as described in the Examples, related molecules are extracted based on the medical information of IPF patients, and ABL, RET, SRC family, ERK1 / 2, and FLT3 have been found as intermediate molecules that control the expression of the relevant molecules. Therefore, any molecule that has the function of inhibiting these five intermediate molecules can function as a therapeutic or preventive agent for IPF according to the present disclosure. For example, such therapeutic or preventive agents include the above-mentioned ABL inhibitors, RET inhibitors, SRC family inhibitors, ERK1 / 2 phosphorylation inhibitors, or FLT3 inhibitors, and preferably ponatinib can be used.

[0043] Considering that nintedanib, which is clinically used as an antifibrotic drug, can also be used to treat IPF, whether there are reports on phenomena related to IPF such as fibrosis and inflammation, and whether more downstream molecules can be simultaneously inhibited by inhibiting the molecule, in one embodiment of the present disclosure, the therapeutic or preventive agent for IPF of the present disclosure preferably has at least the function of an ERK1 / 2 inhibitor or an SRC family inhibitor. In another embodiment, the therapeutic or preventive agent for IPF of the present disclosure preferably has the function of an ERK1 / 2 inhibitor and an SRC family inhibitor. In yet another embodiment, the therapeutic or preventive agent for IPF of the present disclosure preferably includes the function of an FLT3 inhibitor, a RET inhibitor, and / or an ABL inhibitor in addition to the function of an ERK1 / 2 inhibitor and / or an SRC family inhibitor.

[0044] (IPF markers or diagnostic agents) In one aspect of the present disclosure, a marker or diagnostic agent for idiopathic pulmonary fibrosis (IPF) is provided, comprising a hub molecule in a network composed of molecules related to one or more clinical information of idiopathic pulmonary fibrosis (IPF), or a detection agent thereof.

[0045] As shown in the examples, in the present disclosure, an algorithm (subset binding) for linking and detecting a group of items associated with heterogeneous data is used to detect proteins that co-occur with symptoms of IPF (e.g., characteristic image findings, medical records, and / or blood test value data, etc.) from medical information and proteome data. That is, these molecules can be said to be molecules whose expression varies in association with symptoms of IPF, and specifically, such molecules include ANXA7, ITIH1, ITIH2, ITIH3, ITIH4, ITIH5, ITIH6, MRPS17, AGN, SRI, ALOX12, PEF1, PNP, FHL1, PCMT1, PIP4P2, HEBP2, CAPN1, PLXDC2, PTPN6, LYN, TAOK3, RAN, CNP, and MIF.

[0046] In one embodiment, such molecules include ANXA7, ITIH1, ITIH2, ITIH3, ITIH4, ITIH5, ITIH6, MRPS17, SRI, ALOX12, PEF1, PTPN6, LYN, RAN, and MIF. In another embodiment, when investigating how 20 proteins that co-occur with characteristic image findings, medical records, and blood test value data of IPF are related to each other, four molecules that are particularly related to each other can be found, and these molecules can be said to be molecules (hub molecules) that are directly or indirectly related to more molecules among the 20 molecules. Specifically, such hub molecules include LYN, PTPN6, MIF, and RAN.

[0047] In one embodiment of the present disclosure, when clinical information and proteome data are analyzed using subset binding, proteins (core molecules) that co-occur with multiple pieces of clinical information can be obtained. Thus, in one embodiment, the marker or diagnostic agent of the present disclosure can include a molecule associated with multiple pieces of clinical information of idiopathic pulmonary fibrosis (IPF), or a detection agent thereof. Examples of such core molecules include ANXA7, ITIH1, ITIH2, ITIH3, ITIH4, ITIH5, ITIH6, MRPS17, AGN, SRI, ALOX12, and PEF1.

[0048] In one embodiment of the present disclosure, upstream regulatory molecules can be obtained by searching for upstream molecules that control the expression of the above-mentioned core molecules, and the upstream regulatory molecules themselves can be considered to be molecules that are somehow involved in the pathology of IPF. Therefore, the marker or diagnostic agent of the present disclosure can include a molecule that controls the expression of molecules related to multiple medical information of idiopathic pulmonary fibrosis (IPF), or a detection agent thereof, and specifically, such molecules can include ESR1, CCDN1, NOS2, CCR2, PRKAA1, MKNK1, and MMP14.

[0049] In the present disclosure, an algorithm (subset binding) that links and detects a group of items that are related among heterogeneous data is used to detect proteins that co-occur with symptoms of IPF (e.g., characteristic image findings, medical records, and / or blood test value data, etc.) from medical information and proteome data. Therefore, regulators or inhibitors of such molecules can be said to be regulators or inhibitors of molecules related to the symptoms of IPF, and can be used as therapeutic or preventive agents for IPF. Specifically, examples of proteins that co-occur with symptoms of IPF include the molecules exemplified elsewhere in this specification.

[0050] In one embodiment, by searching for the upstream molecule that controls the expression of the above-mentioned core molecule, an upstream control molecule can be obtained, and the upstream control molecule itself can be considered to be a molecule that is somehow involved in the pathology of IPF. Therefore, it is considered that a regulator or inhibitor of such an upstream control molecule also functions as a therapeutic or preventive agent for IPF. Therefore, the therapeutic or preventive agent for IPF of the present disclosure can include a regulator or inhibitor of a molecule related to multiple medical information of IPF, and specifically, such a molecule can include the molecules exemplified in other parts of this specification.

[0051] In one embodiment of the present disclosure, examples of regulators or inhibitors of hub molecules in a network composed of molecules related to one or more clinical information of idiopathic pulmonary fibrosis (IPF) include, but are not limited to, the compounds or drugs listed in the right column of the table below.

[0052] [Table 2A] [Table 2B]

[0053] (Screening Method) In one aspect of the present disclosure, there is provided a screening method for searching for a therapeutic or preventive agent for a certain disease, the method comprising the steps of identifying a molecule having a regulatory effect on a specific network associated with the disease, and confirming whether the molecule functions as a therapeutic or preventive agent for the disease.

[0054] In the present disclosure, an algorithm (subset binding) that links and detects a group of items that are correlated among heterogeneous data can be used to detect proteins that co-occur with symptoms of IPF (e.g., characteristic image findings, medical records, and / or blood test value data, etc.) from medical information and proteome data. Therefore, by using a similar method, it is expected that networks composed of molecules related to other diseases can be found for other diseases, and molecules that compose the networks or molecules that have a regulating effect on the molecules can be identified, which can function as therapeutic or preventive agents for the diseases.

[0055] The method disclosed herein can be useful for patient diagnosis and differentiation without invasive procedures, and can therefore be applied to intractable diseases whose disease onset mechanisms are not fully understood at the molecular level. For example, such diseases include idiopathic interstitial pneumonias (IIPs), whose causes cannot be identified. IIPs are classified as clinicopathological disease entities into idiopathic pulmonary fibrosis (IPF), nonspecific interstitial pneumonia (NSIP), cryptogenic organizing pneumonia (COP, idiopathic bronchiolitis obliterans organizing pneumonia (idiopathic BOOP), acute interstitial pneumonia (AIP), desquamative interstitial pneumonia (DIP), respiratory bronchiolitis associated interstitial lung disease (RB-ILD), lymphocytic interstitial pneumonia (ILD), and idiopathic pulmonary fibrosis (IPF). In the Ministry of Health, Labor and Welfare's specific disease certification criteria, a surgical lung biopsy (SLB) is required to diagnose IIPs other than IPF, such as NSIP and COP, so the method of the present disclosure is particularly useful.

[0056] In one embodiment, whether or not a molecule constituting the above network or a molecule having a regulating effect on the molecule functions as a therapeutic or preventive agent for the disease can be confirmed by, for example, the following methods or a combination thereof: Collect molecular information using existing databases and literature information to confirm its relationship with disease. Confirming the expression of molecules in fibrotic tissues Using existing databases and literature information, we will find compound information related to molecular control. Reproduce the fibrosis phenomenon at the cellular level and confirm the effect of the compound. The network in which the molecule is a component is identified, and it is confirmed whether the network shows abnormalities in the disease.

[0057] In another aspect of the present disclosure, a composition for treating or preventing idiopathic pulmonary fibrosis (IPF) is provided, which comprises an ABL inhibitor, a RET inhibitor, an SRC family inhibitor, an ERK1 / 2 phosphorylation inhibitor, or an FLT3 inhibitor. In one embodiment of the present disclosure, the inhibitors contained in such a composition may be those described elsewhere in this specification.

[0058] In another aspect of the present disclosure, a method for treating or preventing a patient suffering from or at risk of suffering from idiopathic pulmonary fibrosis is provided, comprising administering to said subject an effective amount of an ABL inhibitor, a RET inhibitor, an SRC family inhibitor, an ERK1 / 2 phosphorylation inhibitor, or an FLT3 inhibitor.In one embodiment of the present disclosure, the inhibitors used in such a method can be those described elsewhere in this specification.

[0059] (General technology) The molecular biological, biochemical and microbiological techniques used herein are well known and commonly used in the art, and are described, for example, in Sambrook J. et al. (1989). Molecular Cloning: A Laboratory Manual, Cold Spring Harbor and its 3rd Ed. (2001); Ausubel, FM (1987). Current Protocols in Molecular Biology, Greene Pub. Associates and Wiley-Interscience; Ausubel, FM (1989). Short Protocols in Molecular Biology: A Compendium of Methods from Current Protocols in Molecular Biology, Greene Pub. Associates and Wiley-Interscience; Innis, MA (1990). PCR Protocols: A Guide to Methods and Applications, Academic Press; Ausubel, FM (1992). Short Protocols in Molecular Biology: A Compendium of Methods from Current Protocols in Molecular Biology, Greene Pub. Associates; Ausubel, FM (1995). Short Protocols in Molecular Biology: A Compendium of Methods from Current Protocols in Molecular Biology, Greene Pub. Associates; Innis, MA et al. (1995). PCR Strategies, Academic Press; Ausubel, FM (1999).These methods are described in Short Protocols in Molecular Biology: A Compendium of Methods from Current Protocols in Molecular Biology, Wiley, and annual updates; Sninsky, JJ et al. (1999). PCR Applications: Protocols for Functional Genomics, Academic Press, Special Edition of Experimental Medicine: "Gene Introduction & Expression Analysis Experimental Methods" Yodosha, 1997, etc., and the relevant parts (possibly in their entirety) of these are incorporated herein by reference.

[0060] Regarding DNA synthesis technology and nucleic acid chemistry for producing artificially synthesized genes, gene synthesis and fragment synthesis services such as those of GeneArt, GenScript, Integrated DNA Technologies (IDT), etc. can be used. In addition, for example, Gait, MJ (1985). Oligonucleotide Synthesis: A Practical Approach, IRL Press; Gait, MJ (1990). Oligonucleotide Synthesis: A Practical Approach, IRL Press; Eckstein, F. (1991). Oligonucleotides and Analogues: A Practical Approach, IRL Press; Adams, RL et al. (1992). The Biochemistry of the Nucleic Acids, Chapman & Hall; Shabarova, Z. et al. (1994). Advanced Organic Chemistry of Nucleic Acids, Weinheim; Blackburn, GM et al. (1996). Nucleic Acids in Chemistry and Biology, Oxford University Press; Hermanson, GT (I996). Bioconjugate Techniques, Academic Press, etc., the relevant portions of which are incorporated herein by reference.

[0061] In this specification, "or" is used when "at least one or more" of the items listed in the sentence can be employed. The same applies to "alternative." In this specification, when it is specified that "within the range of" "two values", the range includes the two values ​​themselves. All references cited herein, including scientific literature, patents, patent applications, and the like, are hereby incorporated by reference in their entirety to the same extent as if each was specifically set forth.

[0062] The present disclosure has been described above by showing preferred embodiments for ease of understanding. The present disclosure will be described below based on examples, but the above description and the following examples are provided for illustrative purposes only and are not provided for the purpose of limiting the present disclosure. Therefore, the scope of the present disclosure is not limited to the embodiments or examples specifically described in this specification, but is limited only by the scope of the claims. EXAMPLES

[0063] Example 1: Collection of clinical information The number of patients from whom clinical information (medical information and blood samples) was collected in this example and their characteristics are shown in Table 3. [Table 3]

[0064] The overall flow of data collection is shown in Figure 1A. The collection of medical information (electronic medical record entries, CT image findings, blood biochemistry test values, basic information, and initial consultation questionnaire) and the generation of input data were performed according to the procedure shown in Figure 1B. For example, electronic medical record entries (called medical records) were entered at the time of consultation using a format (called a template) created with pre-defined items, or information was manually extracted from the entries already written in natural language or the initial consultation questionnaire into the template, and collected as structured data. For example, image findings were mechanically extracted by natural language processing to pair information related to the lesion with information on the observed site, and further linked with information on whether the lesion was observed (positive), not observed (negative), or suspected (suspected), and the features were manually corrected and expressed as a one-hot vector for subsequent analysis. Blood test results were also collected as structured data by manually extracting the test values ​​into pre-selected items. The above medical information was collected on the date of blood collection to obtain serum for obtaining proteome data, or on a date close to the date. The proteome data was obtained by isolating exosomes from serum and comprehensively measuring the proteins contained therein by mass spectrometry. Missing values ​​were filled in, and a data set of 6600 x 602 cases of medical information and 2000 x 602 cases of proteome were used for calculation.

[0065] Example 2: Analysis of clinical information and proteomic data The structure of the cohort dataset used in the analysis is shown in Figure 2A, and the analysis workflow is shown in Figure 2B. A newly developed algorithm, subset binding, was used to detect patient stratification rules using structured medical information and proteome data. Subset binding is an algorithm that detects correlated items between heterogeneous data, and aims to obtain patient stratification rules (e.g., patterns such as a tendency for reticular shadowing and traction bronchiectasis to be observed in patients with high expression of biomolecules A, B, and C) in a data-driven manner by detecting correlated items between phenotypic information such as medical information and biomolecular information such as omics data. Subset binding uses fuzzy association rule mining as its base technology, and calculates membership values ​​using a membership function for each of the two input matrices (e.g., proteome data and structured medical information. The rows must be the same, but the number of columns can be different), detects frequent itemsets, and generates association rules by linking the frequent itemsets from both data (Figure 2C). By using this algorithm, it is possible to analyze data that contains a mixture of continuous and discrete values, such as is commonly found in medical information, without the need for special preprocessing or prior knowledge.

[0066] (Example 3: Extraction of disease-related molecules) Table 4 shows the top 20 protein names that co-occurred with characteristic IPF image findings, medical records, and blood test data by subset binding (SB). [Table 4]

[0067] The association with IPF was searched using the Qiagen database and is summarized in Table 5. [Table 5]

[0068] Molecules with no reported associations included MRPS17 (28S ribosomal protein S17, mitochondrial) and PEF1 (Peflin), while molecules with associations with IPF through many molecules included LYN (tyrosine-protein kinase Lyn), PTPN6 (tyrosine-protein phosphatase non-receptor type 6), MIF (macrophagemigration inhibitory factor), and RAN (GTP-binding nuclear protein Ran). In addition, a search for protein interactions among the 20 molecules using TargetMine (data warehouse) revealed that the four molecules with a high association with IPF described above were also hub molecules in the protein interactions of these 20 molecules (Figure 3, Table 6).

[0069] [Table 6]

[0070] Furthermore, pathway analysis was performed using IPA (Ingenuity pathway analysis) using seven proteins (called core molecules) that co-occurred with multiple medical information, and acute phase Response Signaling, Eicosanoid Signaling, Agrin interactions at Neuromuscular Junction, LXR / RXR Activation, FXR / RXR Activation, etc. were extracted as canonical pathways, and Development Disorder, Hereditary Disorder, Immunological Disease, Neurological Disease, Organismal Injury and Abnormalities, etc. were extracted as disease and function pathways.

[0071] Furthermore, by searching for the molecular network that these molecules constitute, we found Carbohydrate Metabolism, Small Molecule Biochemistry, and Cellular Assembly and Organization, where all the molecules are mapped. The regulatory relationships between molecules including the seven core molecules on this network are depicted in Figure 4. In addition, using IPA causal network analysis, we searched for upstream regulatory relationships regarding the expression of the seven core molecules, and as shown in Figure 5, we identified that these molecules are controlled by molecules such as ESR1, CCDN1, CCR2, NOS2, and MMP14, which are controlled by phosphorylation signal-related proteins such as SRC family, ERK1 / 2, and ABL1, and that ponatinib controls these molecules collectively upstream.

[0072] Using the MGI database (URL: http: / / www.informatics.jax.org / ) and the JAXKO mouse phenotype database (URL: https: / / www.jax.org / jax-mice-and-services), we performed a phenotype search for the presence or absence of KO mice of core molecules and hub molecules, and the results are summarized in Table 7. [Table 7]

[0073] LYN and PTPN6 were found to have phenotypes such as inflammation in the lungs, but for other molecules, there was no data or only reports of their effects on other organs.

[0074] Example 4: Expression of molecules in fibrotic tissue Of the 20 molecules presented by SB, seven core proteins and four hub proteins were examined for their expression in the patient's lungs and for their increased expression in fibrotic sites. Fibrotic and normal lung sites of IPF patients who had developed cancer and underwent surgery were examined by immunostaining using primary antibodies. As a result, as shown in the representative staining images in Figure 6, in tissues in which obvious fibrosis was observed by MC (Masson's Trichrome) staining, a clear increase in expression was observed, as shown for Lyn. The results are listed in Table 8.

[0075] [Table 8]

[0076] It was confirmed that the expression of almost all protein molecules, except for ITIH, was increased in fibrotic sites, especially in epithelial cells and inflammatory cells.

[0077] (Example 5: EMT Inhibitory Effect) The importance of epithelial mesenchymal transition (EMT) in the mechanism of pulmonary fibrosis in IPF has been suggested. In this example, we successfully established a test system for inducing EMT with TGF-beta using human normal airway epithelial cells BEAS-2B, and further confirmed the EMT inhibitory effect of ponatinib (Figure 7).

[0078] The importance of epithelial mesenchymal transition (EMT) has been suggested in the mechanism of pulmonary fibrosis in IPF. In this example, in addition to A549 cells, which are generally used for EMT, a system was established to induce EMT by TGF-beta using human normal airway epithelial cells BEAS-2B, and the EMT inhibitory effect of ponatinib was verified. As for nintedanib, EMT inhibitory effect has been reported as one of the mechanisms of its fibrosis inhibitory effect, and the fact that ponatinib, which controls IPF-related molecules upstream, inhibited EMT as found in this example suggests the fibrosis inhibitory effect of ponatinib. In addition, the phenomenon of fibrosis occurs in many organs such as the liver and skin, and there are many patients affected by each. It has also been revealed recently that fibrosis is related to the development of cancer, and in fact, about 30% of IPF cases are accompanied by cancer. Therefore, by exploring targets such as ponatinib based on the elucidation of the nature of fibrosis in IPF, it is expected that it will lead to the development of treatments for many fibrotic diseases in other organs and the elucidation of the mechanisms of cancer development. Further elucidation of molecular mechanisms, such as EMT, metabolic pathway research, and phosphorylation signal research, will contribute to the treatment and early diagnosis of IPF.

[0079] method (Serum collection) (Blood collection, processing, and freezing conditions) Patients aged 16 years or older who were diagnosed with interstitial pneumonia, including IPF, and who received medical treatment at Osaka University Hospital or one of its research partner institutions, were given a thorough explanation by their doctor or a medical specialist based on the "information document," and gave written consent to participate in the study, had 10 mL of blood collected for research purposes during medical treatment. The collected blood was left to stand at room temperature for one hour, then centrifuged at 3000 rpm for 10 minutes, and the supernatant was separated as serum. The separated serum was immediately frozen and stored in a -80°C freezer. Serum was also collected using the same method from those who were diagnosed as not having organic respiratory disease as a result of the test.

[0080] (Proteome analysis protocol) Extracellular vesicles were purified from 200 μl of serum using the MagCapture isolation kit (Fujifilm Wako). Proteins in the extracellular vesicles were reduced with tris(2-carboxyethyl)phosphine, alkylated with iodoacetamide, digested with trypsin, and desalted. The pretreated samples were analyzed by LC-MS / MS using the data independent acquisition (DIA) method. Data analysis was performed using the DIA analysis software Spectranout, with run-wise imputation for missing values. As a quality control, one commercially available serum sample was added to every 15 samples to ensure quality from sample preparation to data analysis. DIA analysis of HeLa cell digests was also performed as a quality control for mass spectrometry.

[0081] (Protocol for collecting medical information) The medical information securely stored in the data center of the Osaka University Hospital was provided to the National Institute of Biomedical Innovation after patient IDs were anonymized and stored on an encrypted hard disk, with the cooperation of the Department of Medical Information at the Osaka University Hospital.

[0082] Of the medical information, the medical records were obtained as structured data by doctors using a template that had been created by listing 102 necessary items of information in advance, or the structured data was created by manually curating the free text data into a template at the National Institute of Biomedical Innovation. For the image findings, important expressions were tagged manually or using natural language processing techniques to obtain structured data consisting of pairs of sites and lesions and three cases in which these pairs were found (positive), not found (negative), or suspected (suspect). For blood test values, 173 important items were selected, curated, and structured. For the initial consultation questionnaire and basic information, information was curated and added to the medical record template items. In addition, in structuring, the meaning of missing values ​​was confirmed, and the missing values ​​were filled in mainly using standard values ​​for healthy individuals.

[0083] (Protocol for NLP of image reading findings) Tagging Protocol We conducted tag classification to assign tags to expressions that appear in clinical texts such as medical records and image findings that correspond to medical concepts such as disease names, illness names, and body part names.

[0084] Following the above tag classification, annotation guidelines were created based on actual examples, and tags and important words were extracted from medical records and radiological findings. The validity of the tags was confirmed by medical experts, and correct answer data was created. Using the obtained corpus, a medical expression recognition and relationship estimation system was set up, and an extraction system was constructed using the Japanese BERT model.

[0085] (subset binding) We proposed the idea of ​​"subset binding," which uses co-occurrence between heterogeneous data to discover mutually related attributes, and developed a new algorithm for subset binding by extending FARM technology. Subset binding uses the FARM (Fuzzy Association Rule Mining) method to search for frequently occurring items from two data sets, proteomic data and medical information, and discovers association rules (patterns of co-occurrence between items within frequent items) so that the antecedent can be obtained from one data set and the consequent from the other data. Proteomic data linked to medical information was analyzed by performing subset binding with the following parameter settings. min support = 0.12, 0.02, 0.02, 0.02 for the proteome, the CT reading report, the EHR, and the blood test, respectively. min number of items = 8, 4, 5, 4 for the proteome, the CT reading report, the EHR, and the blood test, respectively. min lift = 2, 3, 3 for the association rules between proteome - CT reading report, the proteome - EHR, and the proteome - blood test, respectively.

[0086] (IPA) Disease and pathway analysis and network generation were performed using ingenuity pathway analysis (IPA) software (QIAGEN, Redwood City, CA) and the general IPA database, which relies on available publications describing the biological mechanisms, interactions, and functions of proteins. In IPA, the term "upstream regulator" is used to refer to a biomolecule that may affect the expression of another biomolecule, including drugs, chemicals, kinases, receptors, microRNAs, cytokines, or transcription factors.

[0087] (immunostaining) Fibrotic and normal areas of the excised lungs from five IPF patients (currently two) who had developed lung cancer and underwent surgery at Osaka University Hospital were separated and fixed in formalin phosphate buffer.

[0088] Formalin-fixed lung tissue was cut along the long axis of the tissue section to prepare an FFPE (Formalin fixed paraffin embedded) block, which was then sliced ​​to a thickness of 4 μm using a sliding microtome to prepare an unstained specimen. The unstained specimen was stained with hematoxylin and eosin (HE) and Masson's trichrome (MT) to confirm inflammation and fibrosis. In addition, the unstained specimen was stained by IHC (Immunohistochemistry) using specific antibodies for the proteins found by the analysis. The detection reagent was the OptiView DAB Universal Kit, and staining with antibody dilution was also performed simultaneously as a negative control for each antibody to evaluate the IHC staining for each antibody. The stained specimen was photographed using a bright-field slide scanner with a 20x objective lens setting, and the image files were saved in SVS format.

[0089] The stained tissue specimens were examined under a bright-field microscope to evaluate fibrosis and IHC.

[0090] (EMT experiment) Coating agent: Fibronectin / Collagen I / BSA Seeding cell concentration: 2.5×10 4 , 3.5×10 4 cells / mL 24 hours after seeding, TGF-β was added at 3 ng / mL immediately after the drug addition. Cells were harvested 48 hours after addition of TGF-β. The leftmost column of each graph is the complete negative control (no TGF added).

[0091] EMT was evaluated using the suppression of expression of the epithelial marker E-cadherin and the enhancement of expression of the mesenchymal markers Fibronectin and Snail as indicators. 4 Or 3.5 x 10 4 The cells were seeded at 1000 cells / mL (medium; BEGM Bu,lletKit; Bronchial epithelial cell basal medium, Lonza Co., Ltd.) onto a 96-well plate coated with fibronectin / collagen I / BSA, and after 24 hours, the test drug was added, followed by the addition of TGF-β (Proteintech) to a final concentration of 3 ng / mL. 48 hours after the addition of TGF-β, cell lysis and RT were performed using SuperPrep II Cell Lysis & RT Kit for qPCR (Toyobo Co., Ltd.), and the expression levels of the above-mentioned EMT marker genes were measured by qPCR. THUNDERBIRD Probe qPCR Mix (Toyobo Co., Ltd.) was used for qPCR, and TaqMan Probe (Thermo Fisher Scientific Co., Ltd.) was used for each marker probe.

[0092] Example 6: Treatment Example The preventive or therapeutic agent for IPF identified in the above examples (e.g., ponatinib) is administered to the subject (patient or subject expected to be prevented) in a preventive or therapeutic effective amount calculated based on the above examples. If the formulation is already commercially available, that formulation is used, and if not, it is appropriately formulated and used. A single drug or a combination of multiple drugs having one or more functions of an ABL inhibitor, RET inhibitor, SRC family inhibitor, ERK1 / 2 phosphorylation inhibitor, or FLT3 inhibitor is selected.

[0093] The subjects will be monitored over time to confirm improvement or prevention of worsening or onset of the target disease, such as IPF.

[0094] As a result of the above, the effectiveness of the therapeutic or prophylactic agent identified in the present disclosure can be confirmed.

[0095] (Note) Although the present disclosure has been illustrated using the preferred embodiments thereof, it is understood that the present disclosure should be interpreted in scope only by the claims. It is understood that the patents, patent applications, and other documents cited in this specification are incorporated by reference into this specification in the same manner as if the contents themselves were specifically set forth herein. [Industrial Applicability]

[0096] According to the present disclosure, since it is possible to perform data-driven drug discovery target search using human data, it is possible to perform drug discovery target search even for intractable diseases whose disease onset mechanisms are not fully understood at the molecular level. Therefore, applications in the medical field are expected.

Claims

1. An agent for treating or preventing idiopathic pulmonary fibrosis (IPF), comprising an ABL inhibitor, a RET inhibitor, an SRC family inhibitor, an ERK1 / 2 phosphorylation inhibitor, or an FLT3 inhibitor.

2. The therapeutic or prophylactic agent according to claim 1 , which has a function as an inhibitor of at least two of an ABL inhibitor, a RET inhibitor, an SRC family inhibitor, an ERK1 / 2 phosphorylation inhibitor, and an FLT3 inhibitor.

3. The therapeutic or prophylactic agent according to claim 1 or 2, which has functions as an ABL inhibitor, a RET inhibitor, an SRC family inhibitor, an ERK1 / 2 phosphorylation inhibitor, and an FLT3 inhibitor.

4. The therapeutic or prophylactic agent according to any one of claims 1 to 3, comprising ponatinib.

5. A composition comprising an ABL inhibitor, a RET inhibitor, an SRC family inhibitor, an ERK1 / 2 phosphorylation inhibitor, or an FLT3 inhibitor for treating or preventing idiopathic pulmonary fibrosis (IPF).

6. The composition according to claim 5, comprising a drug having inhibitory functions of at least two or more of an ABL inhibitor, a RET inhibitor, an SRC family inhibitor, an ERK1 / 2 phosphorylation inhibitor, and an FLT3 inhibitor.

7. The composition according to claim 5 or 6, wherein the composition comprises a drug having functions as an ABL inhibitor, a RET inhibitor, an SRC family inhibitor, an ERK1 / 2 phosphorylation inhibitor, and an FLT3 inhibitor.

8. The composition of any one of claims 5 to 7, comprising ponatinib.

9. A marker or diagnostic agent for idiopathic pulmonary fibrosis (IPF), comprising a hub molecule in a network composed of molecules related to one or more clinical information of idiopathic pulmonary fibrosis (IPF), or a detection agent thereof.

10. The marker or diagnostic agent of claim 9, wherein the molecule is one or more molecules selected from the group consisting of ANXA7, ITIH1, ITIH2, ITIH3, ITIH4, ITIH5, ITIH6, MRPS17, AGN, SRI, ALOX12, PEF1, PNP, FHL1, PCMT1, PIP4P2, HEBP2, CAPN1, PLXDC2, PTPN6, LYN, TAOK3, RAN, CNP, and MIF.

11. The marker or diagnostic agent of claim 9 or 10, wherein the molecule is selected from the group consisting of ANXA7, ITIH1, ITIH2, ITIH3, ITIH4, ITIH5, ITIH6, MRPS17, SRI, ALOX12, PEF1, PTPN6, LYN, RAN, and MIF.

12. The marker or diagnostic agent according to any one of claims 9 to 11, wherein the molecule is selected from the group consisting of LYN, PTPN6, MIF, and RAN.

13. The marker or diagnostic agent of claim 9, comprising a molecule associated with multiple clinical information of idiopathic pulmonary fibrosis (IPF), or a detection agent thereof.

14. The marker or diagnostic agent of claim 13, wherein the molecule is one or more molecules selected from the group consisting of ANXA7, ITIH1, ITIH2, ITIH3, ITIH4, ITIH5, ITIH6, MRPS17, AGN, SRI, ALOX12, and PEF1.

15. The marker or diagnostic agent according to any one of claims 9 to 14, wherein the medical information includes characteristic image findings, medical records, and / or blood test values ​​of IPF.

16. A marker or diagnostic agent for idiopathic pulmonary fibrosis (IPF), comprising a molecule that controls the expression of molecules related to multiple clinical information of idiopathic pulmonary fibrosis (IPF), or a detection agent thereof.

17. The marker or diagnostic agent of claim 16, wherein the molecule is one or more molecules selected from the group consisting of ESR1, CCDN1, NOS2, CCR2, PRKAA1, MKNK1, and MMP14.

18. A therapeutic or preventive agent for idiopathic pulmonary fibrosis (IPF), comprising a regulator or inhibitor of a hub molecule in a network formed by molecules related to one or more clinical information of IPF.

19. The therapeutic or prophylactic agent of claim 18, wherein the molecule is one or more molecules selected from the group consisting of ANXA7, ITIH1, ITIH2, ITIH3, ITIH4, ITIH5, ITIH6, MRPS17, AGN, SRI, ALOX12, PEF1, PNP, FHL1, PCMT1, PIP4P2, HEBP2, CAPN1, PLXDC2, PTPN6, LYN, TAOK3, RAN, CNP, and MIF.

20. The therapeutic or prophylactic agent according to claim 18 or 19, wherein the molecule is selected from the group consisting of ANXA7, ITIH1, ITIH2, ITIH3, ITIH4, ITIH5, ITIH6, MRPS17, SRI, ALOX12, PEF1, PTPN6, LYN, RAN, and MIF.

21. The method of any one of claims 18 to 20, wherein the molecule is selected from the group consisting of LYN, PTPN6, MIF, and RAN.

22. The therapeutic or prophylactic agent according to claim 18, comprising a regulator or inhibitor of a molecule associated with multiple clinical information of idiopathic pulmonary fibrosis (IPF).

23. The therapeutic or prophylactic agent according to claim 22, wherein the molecule is one or more molecules selected from the group consisting of ANXA7, ITIH1, ITIH2, ITIH3, ITIH4, ITIH5, ITIH6, MRPS17, AGN, SRI, ALOX12, and PEF1.

24. The therapeutic or prophylactic agent according to any one of claims 18 to 23, wherein the medical information includes characteristic image findings, medical records, and / or blood test values ​​of IPF.

25. The therapeutic or prophylactic agent according to any one of claims 18 to 24, wherein the regulator or inhibitor comprises a compound or drug described in the right column of the table below. 【Table 1A】 【Table 1B】

26. A screening method for discovering a therapeutic or preventive agent for a certain disease, comprising: Identifying molecules that have a regulatory effect on specific networks associated with the disease; determining whether said molecule functions as a therapeutic or preventative agent for said disease; A method comprising:

27. The method of claim 26, wherein the network is constructed based on one or more clinical information of the disease.

28. The method of claim 27 , wherein the medical information includes image findings, medical records, and / or blood test values ​​characteristic of the disease.

29. The step of confirming comprises: (a) collecting information on the molecule using existing databases and / or literature information and confirming its relationship with the disease; (b) confirming the expression of the molecule in fibrotic tissue; (c) searching for information on compounds related to the regulation of the molecule using existing databases and / or literature information; (d) reproducing the fibrosis phenomenon at the cellular level and confirming the action of the molecule; and / or (e) identifying a network formed by the molecules and determining whether the network shows an abnormality in the disease; The method according to any one of claims 26 to 28, wherein the method is carried out by any one or more of the following:

30. 30. The method of any one of claims 26 to 29, wherein the disease comprises idiopathic pulmonary fibrosis (IPF).

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