Application of TAK875 in preparation of STAT3 inhibitor

Abstract

The invention provides application of TAK875 in preparation of an STAT3 inhibitor, and belongs to the field of biological medicine. Researches find that TAK875 can inhibit phosphorylation of STAT3 so as to inhibit transcriptional activity of STAT3, and TAK875 is a novel STAT3 small-molecule inhibitor; besides, TAK875 shows remarkable anti-tumor and anti-inflammatory activity in vivo and in vitro, can be used for preparing anti-tumor and anti-inflammatory drugs, and has a good application prospect.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine, and particularly relates to the use of TAK875 in the preparation of STAT3 inhibitors. Background Art

[0002] Signal transducer and activator of transcription (STATs) is a family of transcription factors that can be activated by extracellular signal ligands such as cytokines, growth factors, and hormones, transmit signals from cytokine receptors and growth factor receptors to the nucleus, mediate the cell's response to cytokines, growth factors, and hormones, and participate in transmitting extracellular stimuli and regulating various biological processes, including cell growth and differentiation, as well as inflammation and immune responses. During normal development, the activation of STATs in mammalian cells is rapid and transient, and gene transcription is highly strictly regulated.

[0003] Signal transducer and activator of transcription 3 (STAT3) in the STAT family plays a dual role as a signal transducer and a transcription factor. STAT3 has a common structural motif with other STAT proteins, and the C-terminal transcriptional activation domain contains conserved tyrosine (Tyr705) residues and serine residues (S727) that are crucial for STAT3 activation. In the classical STAT3 activation pathway, cytoplasmic STAT3 monomers are activated by phosphorylation of Tyr705 by many key kinases associated with growth factor receptors (including Janus kinases, cytokine receptors, and toll-like receptors), form homodimers mediated by SH2 domains in a head-to-tail pattern, and then translocate into the nucleus and bind to specific DNA fragments (TTCNNNGAA) of the target gene promoter, and then promote the transcription of many downstream target genes such as Bcl-XL, MMPs, Mcl-1, and vascular endothelial growth factor (VEGF), regulate the expression of many key genes involved in cell cycle progression, proliferation, differentiation, migration, and invasion, and play a crucial role in processes such as cell growth and apoptosis. Phosphorylation at STAT3 Ser727 is necessary for the full transcriptional activity of STAT3.

[0004] STAT3 serine phosphorylation may occur in response to various stimuli and regulate its transcriptional activity. Different from the typical role of STAT3 phosphorylation at Tyr705, phosphorylation of Ser727 mainly regulates the mitochondrial function of tumor cells. The recent report of the discovery of mitochondrial STAT3 (mSTAT3) has revealed its new role and provided a link between oncogene-induced cell signaling pathways and cancer cell metabolism. Mitochondrial complexes I and II contain gene 19 related to retinoic acid-interferon-induced cell death (GRIM-19), which are components of the electron transport chain (ETC) and generate energy through oxidative phosphorylation (OXPHOS). Mitochondrial STAT3 is present on the inner membrane of mitochondria, binds to electron transport chain complex I (ETC I) on the inner membrane, and participates in regulating processes such as mitochondrial bioenergetic metabolism and apoptosis. In the non-classical STAT3 activation pathway, p-STAT3 (S727) activates mitochondrial mSTAT3, and GRIM-19 imports STAT3 into mitochondria. The upregulation of mSTAT3 increases the activities of mitochondrial complexes I and II, thereby increasing OXPHOS. Functionally, mSTAT3 enhances ETC activity; ATP production in cells lacking mSTAT3 is significantly reduced. The upregulation of mitochondrial STAT3 and OXPHOS is a resistance mechanism to TKI treatment. In cells under oxidative stress, functional mSTAT3 plays a crucial role in preventing ROS-induced ASK1 / p38MAPK-mediated apoptosis. In addition, functional mSTAT3 is required for the malignant transformation of protein tyrosine kinase oncoproteins (such as anaplastic lymphoma kinase (ALK) and v-Src) and oncogenes lacking tyrosine kinase activity (such as the RAS oncogene). A preclinical study has shown that in some cases, mSTAT3 plays a more critical role in malignant transformation than classical STAT3 activation, such as Barrett cells with oncogenic H-RasG12V.

[0005] In normal cells, the activation of STAT3 is strictly regulated by many signaling mechanisms. However, constitutive STAT3 activation is a hallmark of multiple human cancers and is associated with worse clinicopathological phenotypes, clinical disease progression, and advanced tumor metastasis. Constitutive activation of STAT3 and other family members has been detected in a variety of human tumor specimens and cancer cell lines, including multiple myeloma, leukemia, prostate cancer, breast cancer, colorectal cancer, head and neck squamous cell carcinoma (SCCHN), liver cancer, glioma, lung cancer, lymphoma, and nasopharyngeal carcinoma. Although there is a large body of evidence linking the pharmacological or genetic effects of constitutively active STAT3 to tumor phenotypes and progression in vivo, the exact mechanism by which STAT3 induces tumor formation has not been fully established. Increased expression of human epidermal growth factor receptor (EGFR), tyrosine kinase Src, or JAK proteins, resulting in overactivation mutations, are factors that have been proposed to explain constitutive phosphorylation of STAT3. The levels of STAT3-activating ligands such as TGFα and IL-6 are also increased in the serum or tumors of patients with various types of human cancers. Additionally, decreased expression of STAT3 negative regulators (such as PTP, PIAS, or SOCS proteins) may also promote overactivation of STAT3, thereby promoting tumor growth.

[0006] Growing evidence indicates that aberrantly activated STAT3 can mediate tumorigenesis and malignant transformation by regulating tumor growth, survival, apoptosis, angiogenesis, and metastasis. Sustained STAT3 activation induces the overexpression of abnormal downstream signals, such as c-Myc, survivin, cyclin D1, Bcl-2, and some other oncogenes involved in tumor development. STAT3 participates in tumorigenesis by initiating the cell cycle, preventing apoptosis, and upregulating the levels of Bcl-2 (inhibiting apoptosis) and c-Myc (regulating the cell cycle), promoting tumor growth. High levels of expression of the anti-apoptotic protein Bcl-2 are associated with disease progression and poor prognosis in a variety of tumors. The mechanisms of tumorigenesis mediated by constitutively active STAT3 also include regulating the expression of pro-inflammatory cytokines, inhibiting tumor immune surveillance to promote tumor progression.

[0007] Inhibiting constitutive STAT3 signaling in various types of tumor cells through STAT3 antisense oligonucleotides, STAT3 small interfering RNA (siRNA), gene knockout of STAT3, or stable transfection of dominant-negative STAT3 mutants, and downregulating the expression of target genes responsible for regulating the cell cycle, apoptosis, and various cellular physiological functions, have been shown to inhibit cancer cell growth, invasion, and metastasis, and induce apoptosis in preclinical models. Recent studies have found that STAT3 is involved in the regulation of the tumor microenvironment and tumor stem cells, and the activation of STAT3 is associated with the promotion and maintenance, tumorigenicity, and metastatic ability of cancer stem-like cells (CSCs) in many human cancers. Inhibition of STAT3 in normal cells leads to growth arrest but not apoptosis, indicating that STAT3 preferentially exerts its inhibitory effect on constitutively activated STAT3 in cancer cells. In summary, STAT3 is a potential anti-cancer therapeutic target, and directly targeting abnormal STAT3 signaling is a potential therapeutic strategy for most human cancers with constitutive activation of STAT3.

[0008] In addition, STAT3 has protective and anti-inflammatory effects. In T cells, STAT3 plays a key role in the pathogenesis of UC and CD, and overactivation is associated with an increase in Th17 responses and intestinal inflammation. Multiple studies on T cell-related STAT3 signal transduction have shown that the levels of STAT3 and phosphorylated STAT3 are both elevated in mucosal tissue samples from patients with UC and CD. In addition, transcriptomic and proteomic analyses of colon biopsy samples have shown that the inflammatory response of the IL-6-JAK / STAT3 signaling pathway is positively enriched in CD and UC samples. In conditional gene knockout mice, overactivation of STAT3 can overcome the inhibitory effect of suppressor of cytokine signaling 3 (SOCS3) (SOCS3 promotes severe colitis) and inhibit STAT3-induced apoptosis of lamina propria cells, thereby improving colitis. Similarly, mice conditionally deficient in STAT3 (especially IECs) are more susceptible to dextran sulfate sodium (DSS)-induced colitis.

[0009] Targeting STAT3 is a promising strategy for the treatment of IBD. Due to the direct regulatory effect of transcription factors on target genes, compared with upstream signaling proteins such as kinases, transcription factors have higher disease regulation specificity, thus reducing side effects caused by crosstalk in signaling pathways, providing new ideas and hope for the development of small molecule drugs.

[0010] TAK875 (Fasiglifam) is a new drug for the treatment of type 2 diabetes and the most advanced GPR40 agonist, and its structure is shown below. There is currently no report on its anti-tumor and anti-colitis activities targeting the STAT3 target.

[0011] Summary of the Invention

[0012] The object of the present invention is to provide the use of TAK875 in the preparation of STAT3 inhibitors. As a STAT3 inhibitor, TAK875 can be used in the preparation of anti-tumor and anti-inflammatory drugs.

[0013] The present invention provides the use of TAK875 or its salt in the preparation of STAT3 inhibitors, and the structure of the said TAK875 is shown as follows:

[0014]

[0015] Furthermore, the STAT3 inhibitor is an inhibitor that inhibits the transcriptional activity of STAT3.

[0016] Furthermore, the STAT3 inhibitor is an inhibitor that inhibits the phosphorylation of STAT3.

[0017] Furthermore, the STAT3 inhibitor is an inhibitor that inhibits the formation of STAT3 dimers.

[0018] The present invention also provides the use of TAK875 or its salt in the preparation of drugs for preventing and / or treating STAT3-related diseases, and the structure of the said TAK875 is shown as follows:

[0019]

[0020] Furthermore, the drug is an anti-tumor or anti-inflammatory drug.

[0021] Furthermore, the anti-tumor drug is a drug that inhibits the growth, proliferation, migration, and invasion of tumor cells;

[0022] Preferably, the tumor is liver cancer, colorectal cancer, colon cancer, rectal cancer, gastric cancer, pancreatic cancer, esophageal cancer, lung cancer, mediastinal tumor, cervical cancer, head and neck tumor, melanoma, glioblastoma, breast cancer, ovarian cancer.

[0023] Furthermore, the anti-inflammatory drug is a drug that inhibits the release of inflammatory factors.

[0024] Furthermore, the anti-inflammatory drug is a drug for treating colitis, Crohn's disease, psoriasis, rosacea, atopic dermatitis, pulmonary fibrosis, renal fibrosis, myocardial fibrosis, senile deafness, Alzheimer's disease;

[0025] Preferably, the colitis is ulcerative colitis, acute colitis.

[0026] Furthermore, the drug comprises TAK875 or a salt thereof and one or more pharmaceutically acceptable carriers.

[0027] The research of the present invention found that in an in vitro JAK / STAT3 firefly luciferase reporter gene screening model, TAK875 (Fasiglifam) can significantly inhibit the transcriptional activity of STAT3. SPR and ITC experiments both showed that TAK875 (Fasiglifam) directly interacts with STAT3. Therefore, it can be used as a novel small molecule inhibitor of STAT3 for drug preparation.

[0028] The research of the present invention also found that TAK875 has inhibitory activity against a variety of tumor cells, and its IC50 is 15 μM - 40 μM. In addition, TAK875 can inhibit the release of nitric oxide (NO), inducible nitric oxide synthase (iNOS) and inflammatory factors in LPS- and IFN-γ-induced RAW264.7 cells, and at the same time has a significant preventive and alleviating effect on DSS-induced acute colitis in mice. Therefore, TAK875 can be used as a novel STAT3 inhibitor for the preparation of drugs in the anti-tumor and anti-inflammatory fields.

[0029] In summary, the research of the present invention found that TAK875 can inhibit the phosphorylation of STAT3, thereby inhibiting the transcriptional activity of STAT3, and it is a novel small molecule inhibitor of STAT3. In addition, TAK875 shows significant anti-tumor and anti-inflammatory activities in vitro and in vivo, and can be used for the preparation of anti-tumor and anti-inflammatory drugs, having good application prospects.

[0030] Obviously, based on the above content of the present invention, according to the common general technical knowledge and customary means in the art, without departing from the above basic technical idea of the present invention, various other forms of modifications, substitutions or changes can be made.

[0031] The following is a further detailed description of the above content of the present invention through specific embodiments in the form of examples. However, this should not be understood as limiting the scope of the above subject matter of the present invention to the following examples. All technologies implemented based on the above content of the present invention belong to the scope of the present invention. Description of the Drawings

[0032] Figure 1 It is the result of 5 μM TAK875 (Fasiglifam) inhibiting the transcriptional activity of STAT3 in HEK293-SOCS3-Luc cells in Example 1.

[0033] Figure 2 It is the result of the effect of different concentrations of TAK875 (Fasiglifam) on the protein levels of p-STAT3 and STAT3 in HeLa cells in Example 2.

[0034] Figure 3 For the inhibitory effect of TAK875 on different tumor cells in Example 3.

[0035] Figure 4 For the effect of TAK875 (Fasiglifam) on the levels of pro-inflammatory factors in LPS- and IFN-γ-induced RAW264.7 cells in Example 4.

[0036] Figure 5 For the results of the effect of TAK875 (Fasiglifam) on DSS-induced acute colitis in mice in Example 5. Detailed implementation mode

[0037] The raw materials and equipment used in the present invention are all known products, obtained by purchasing commercially available products.

[0038] Example 1. Determination of the effect of TAK875 (Fasiglifam) on STAT3 transcriptional activity

[0039] Drugs and reagents: TAK875 (Fasiglifam) was purchased from APExBIO, Luciferase reporter assay was purchased from Novoprotein, Dulbecco’s Modified Eagle Medium was purchased from Gibco, hygromycin B was purchased from MCE, fetal bovine serum was purchased from Natocor, human LIF protein was purchased from Sino Biological, and DMSO was purchased from Sigma.

[0040] Test cells: HEK293-SOCS3-Luc cells, sourced from Jian Aishi Biomedical Technology (Hangzhou) Co., Ltd.

[0041] Instrument: BioTek Cytation 5 high-throughput live cell microplate detection system.

[0042] Culture medium preparation: Dulbecco's Modified Eagle Medium, supplemented with 100 μg / mL hygromycin B and 10% fetal bovine serum.

[0043] Experimental steps: 1) HEK293-SOCS3-Luc cells were seeded at 1×10 4Cells were inoculated at a density of cells / well in a 96-well plate and grown overnight. 2) After pretreatment with 5 μM TAK875 (Fasiglifam) for 1 hour, 50 ng / mL human LIF protein was added and the cells were stimulated for 4 hours. 3) The culture medium was discarded, and 20 μL of lysis buffer was added to each well to lyse the cells for 30 minutes. 4) 100 μL of luciferase assay reagent was added to each well, and the luminescence signal was detected using a BioTek Cytation5. DMSO was used as the solvent for dissolving TAK875 in the experiment.

[0044] Experimental results: Stimulation of cells with human LIF protein enhanced the transcriptional activity of STAT3. Figure 1 In the figure, DMSO represents the result of treating cells with only DMSO, without adding TAK875 and without stimulating with human LIF protein; LIF represents the result of treating cells with DMSO and then stimulating with human LIF protein without adding TAK875. As Figure 1 shown, 5 μM TAK875 (Fasiglifam) can inhibit the enhanced transcriptional activity of STAT3 stimulated by human LIF protein, and the inhibition rate of STAT3 transcriptional activity exceeds 60%, making it a potential small molecule inhibitor targeting STAT3.

[0045] Example 2. Effect of TAK875 (Fasiglifam) on STAT3 phosphorylation in HeLa cells

[0046] Drugs and reagents: TAK875 (Fasiglifam) was purchased from APExBIO, Dulbecco’s Modified Eagle Medium was purchased from Gibco, fetal bovine serum was purchased from Natocor, penicillin-streptomycin solution, RIPA lysis buffer, and protease inhibitor were purchased from Beyotime, BCA protein concentration assay kit was purchased from Boster, anti-STAT3 and anti-β-actin were purchased from CST, and anti-Phospho-STAT3 (Tyr705) was purchased from HUABIO.

[0047] Instruments: Automatic chemiluminescence image analysis system (Tanon 5200), microplate reader, shaker, centrifuge (Thermo).

[0048] Experimental procedure: 1) HeLa cells were seeded at a density of 4×10 5Cells were seeded at a density of [[number of cells or pores]] per well in a 6-well plate and grown overnight. 2) After treatment with different concentrations (0 μM, 10 μM, 20 μM, and 40 μM) of TAK875 for 24 h, the cells were treated with RIPA lysis buffer supplemented with 1% protease inhibitor to extract total protein. 3) The lysate was centrifuged at 12,000 × g for 10 minutes at 4 °C. Subsequently, the supernatant was collected and its concentration was evaluated using a BCA protein concentration assay kit. 4) SDS-PAGE electrophoresis. 5) The proteins were transferred from the electrophoresis gel to a PVDF membrane. 6) After blocking with 5% non-fat milk in PBST buffer, the primary antibody was incubated overnight at 4 °C. 7) The membrane was washed three times with PBST, and the secondary antibody was incubated for 1 hour at room temperature. 8) Chemiluminescence detection.

[0049] Experimental results: As Figure 2 shown, TAK875 (Fasiglifam) inhibited the phosphorylation of STAT3 in a concentration-dependent manner and slightly affected the total STAT3 level at high concentrations.

[0050] Example 3. Inhibitory effect of TAK875 on different tumor cells

[0051] Drugs and reagents: TAK875 (Fasiglifam) was purchased from APExBIO, Dulbecco’s Modified Eagle Medium was purchased from Gibco, penicillin-streptomycin solution was purchased from Beyotime, and fetal bovine serum was purchased from Natocor.

[0052] Experimental procedure: The CCK8 method was used to evaluate the toxicity of TAK875 to various tumor cells. After co-incubating the corresponding cells with the drug TAK875 in a 96-well plate at 37 °C for 24 h, 48 h, and 72 h, 10 μL of CCK-8 solution was added respectively and incubated at 37 °C for 2 - 4 h. The absorbance at 570 nM was measured using a microplate reader, and the cell inhibition rate = (OD of the blank control group 570 - OD of the experimental group 570 ) / OD of the blank control group 570 × 100%, and the corresponding IC50 value was fitted according to the inhibition rates at different concentrations.

[0053] Experimental results: As Figure 3 shown, TAK875 had an inhibitory effect on various tumor cells (lung cancer A549 cells, cervical cancer Hela cells, breast cancer MDA-MB-231 cells, colon cancer CT26 cells, ovarian cancer SKOV3 cells, and colon cancer HCT116 cells).

[0054] Example 4. Effect of TAK875 (Fasiglifam) on pro-inflammatory factors in LPS- and IFN-γ-induced RAW264.7 cells

[0055] Drugs and reagents: TAK875 (Fasiglifam) was purchased from APExBIO, Dulbecco’s Modified Eagle Medium was purchased from Gibco, penicillin-streptomycin solution was purchased from Beyotime, fetal bovine serum was purchased from Natocor, LPS was purchased from Solarbio, IFN-γ was purchased from Sino Biological, and IL-6, TNF-α, IL-1β ELISA kits were purchased from Ruixin Biotech.

[0056] Instruments: Microplate reader (Rayto RT-6100).

[0057] Experimental procedures: 1) RAW264.7 cells were seeded in 6-well plates at a density of 1×10 5 cells per well and cultured overnight. The cells were treated with different concentrations (0 μM, 10 μM, 20 μM) of TAK875 (Fasiglifam) for 1 hour, and then stimulated with 1 μg / mL of LPS and 20 ng / mL of IFN-γ for 24 hours. The supernatant was aspirated. 2) Coating: The antibody was diluted with 0.05 M pH 9.6 carbonate coating buffer to a protein content of 1 - 10 μg / ml. 0.1 ml was added to each reaction well of the polystyrene plate and incubated overnight at 4°C. The next day, the solution in the wells was discarded and washed 3 times with washing buffer, 3 minutes each time. 3) Sample addition: 0.1 ml of a certain dilution of the sample to be tested was added to the above-coated reaction wells and incubated at 37°C for 1 hour. Then it was washed. 4) Addition of enzyme-labeled antibody: 0.1 ml of freshly diluted enzyme-labeled antibody (dilution after titration) was added to each reaction well. Incubated at 37°C for 0.5 - 1 hour and washed. 5) Addition of substrate solution for color development: 0.1 ml of freshly prepared TMB substrate solution was added to each reaction well and incubated at 37°C for 10 - 30 minutes. 6) Termination of reaction: 0.05 ml of 2 M sulfuric acid was added to each reaction well. 7) Result determination: The absorbance was measured at a wavelength of 540 nm using a microplate reader.

[0058] Experimental results: As Figure 4 shown, TAK875 (Fasiglifam) dose-dependently inhibited the levels of pro-inflammatory factors IL-6, TNF-α, and IL-1β. Therefore, it was determined that TAK875 (Fasiglifam) has a certain anti-inflammatory effect and can be used for the development of anti-inflammatory drugs.

[0059] Example 5. Effect of TAK875 (Fasiglifam) on DSS-induced acute colitis in mice

[0060] Drugs and reagents: TAK875 (Fasiglifam) was purchased from APExBIO, Dextran sulfate sodium salt (DSS) was purchased from MP Biomedicals.

[0061] Animals: Male C57BL / 6 mice at 6 - 8 weeks old, purchased from the Experimental Animal Center of Sichuan University.

[0062] Experimental protocol: To induce experimental colitis, mice were given 2.5% (w / v) Dextran sulfate sodium salt (DSS) in their natural drinking water for 5 consecutive days. Mice in the experimental group were orally administered TAK875 (Fasiglifam) once a day (20 and 30 mg / kg, dissolved in physiological saline containing 10% DMSO and 30% HS - 15) for 8 days (from day 1 to day 8). Tofacitinib was used as a positive control, 20 mg / kg, twice a day. Body weight, fecal consistency, and presence of obvious bleeding were evaluated daily. The Disease Activity Index (DAI) was calculated according to the following formula: DAI = body weight loss score + fecal viscosity score + fecal occult blood score. The scoring details are shown in Table 1 below:

[0063] Table 1. Scoring details

[0064]

[0065] After sacrificing the mice, the colon length was measured. All animal experiments were conducted in accordance with the guiding principles of the Animal Committee of Sichuan University.

[0066] Experimental results: Figure 5 Among them, Wild Type is normal mice; DSS is mice after inducing experimental colitis, and this mouse is not treated with drugs; DSS + Tofacitinib is mice after inducing experimental colitis, and this mouse is treated with tofacitinib; DSS + TAK875 20 mg / kg is mice after inducing experimental colitis, and this mouse is treated with TAK875 (20 mg / kg); DSS + TAK875 30 mg / kg is mice after inducing experimental colitis, and this mouse is treated with TAK875 (30 mg / kg). As shown by Figure 5 it, TAK875 has a significant alleviating effect on DSS - induced acute colitis in mice. TAK875 reduced the weight loss and colon length shortening caused by DSS - induced colitis. Therefore, it was determined that TAK875 has a certain anti - colitis effect and can be used for the development of anti - inflammatory drugs.

[0067] In summary, the research of the present invention found that TAK875 can inhibit the phosphorylation of STAT3, thereby inhibiting the transcriptional activity of STAT3, and it is a novel small - molecule inhibitor of STAT3; in addition, TAK875 exhibits significant anti - tumor and anti - inflammatory activities in vitro and in vivo, can be used for the preparation of anti - tumor and anti - inflammatory drugs, and has good application prospects.

Claims

1. Use of TAK875 or its salt in the preparation of a STAT3 inhibitor, wherein the structure of TAK875 is as follows:

2. The use according to claim 1, characterized in that: The STAT3 inhibitor is an inhibitor that inhibits the transcriptional activity of STAT3.

3. The use according to claim 1, characterized in that: The STAT3 inhibitor is an inhibitor that inhibits STAT3 phosphorylation.

4. The use according to claim 1, characterized in that: The STAT3 inhibitor is an inhibitor that inhibits the formation of STAT3 dimers.

5. Use of TAK875 or its salt in the preparation of a drug for preventing and / or treating a disease associated with STAT3, wherein the structure of TAK875 is as follows:

6. The use according to claim 5, characterized in that: The drug is an anti-tumor or anti-inflammatory drug.

7. The use according to claim 6, characterized in that: The anti-tumor drug is a drug that inhibits the growth, proliferation, migration and invasion of tumor cells; Preferably, the tumor is liver cancer, colorectal cancer, colon cancer, rectal cancer, gastric cancer, pancreatic cancer, esophageal cancer, lung cancer, mediastinal tumor, cervical cancer, head and neck tumor, melanoma, glioma, breast cancer, or ovarian cancer.

8. The use according to claim 6, characterized in that: The anti-inflammatory drug is a drug that inhibits the release of inflammatory factors.

9. The use according to claim 8, characterized in that: The anti-inflammatory drug is a drug for treating colitis, Crohn's disease, psoriasis, rosacea, atopic dermatitis, pulmonary fibrosis, renal fibrosis, myocardial fibrosis, senile deafness, and Alzheimer's disease; Preferably, the colitis is ulcerative colitis or acute colitis.

10. The use according to any one of claims 5 to 9, characterized in that: The drug comprises TAK875 or a salt thereof and one or more pharmaceutically acceptable carriers.

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