Novel targeted inhibition drug and application thereof in preparation of preparation for preventing and treating pancreatic cancer

Abstract

The invention belongs to the technical field of biological medicine, and discloses a novel targeted inhibition drug and application thereof in preparation of a preparation for preventing and treating pancreatic cancer. The drug belongs to a novel azetidine compound, is a targeted inhibitor of STAT3, can be directly applied to preparation of drugs for preventing and treating pancreatic cancer, and provides a new approach and technical thought for treating pancreatic cancer. According to the present invention, the international general pancreatic cancer molding method is adopted, and the experiment conclusion shows that the compound can effectively inhibit the tumor growth state of the nude mouse pancreatic cancer, inhibit the expression of the cell growth-related protein, inhibit the mitochondrial compound enzyme activity and induce the cell apoptosis, and has significant prevention and treatment effects on the pancreatic cancer; the compound is expected to become a novel medicine for treating pancreatic cancer.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of biological medicine, and particularly relates to a novel targeted inhibiting drug and application thereof in preparation of a preparation for preventing and treating pancreatic cancer. BACKGROUND

[0002] Pancreatic cancer is a common malignant tumor of pancreas, and its incidence rate has shown an upward trend in recent years. Pancreatic cancer has high malignancy and short disease course. Generally, when symptoms appear, it is already in the late stage, and metastasis occurs soon, and adjacent organs are invaded. Due to various clinical manifestations and lack of specificity, early diagnosis is difficult, and the treatment effect is not ideal, and the current five-year survival rate is low.

[0003] The pathogenesis of pancreatic cancer is mainly environmental factors, genetic factors and chronic inflammation, and the pathogenesis is that acute injury gradually turns into chronic stage after clinical acute injury, finally induces harmful mutation, and malignant tumor appears in the patient's body. After being recognized by the immune system, there are three consequences of cancer cells and body dynamic balance, cancer cells being eliminated, and cancer cells forming immune escape. If the early mutated cells are destroyed by immune inflammatory cells, immune elimination will be formed. If elimination is not complete, a dynamic balance will be formed between the uneliminated mutated cells and the immune system. When new mutated cells continuously accumulate and the immune response is severely unbalanced, tumor cells will appear resistance. At the same time, the immune inflammatory cells will appear immune suppression signal, and even will secrete factors that invade inflammatory cytokines and promote tumor cell secretion, finally produce high levels of immune suppression factors in the microenvironment, promote tumor cell immune escape, and make pancreatic cancer further deteriorate and develop.

[0004] The treatment of pancreatic cancer includes surgery, radiotherapy, chemotherapy and biological therapy, but effective treatment mainly includes comprehensive treatment of surgery, radiotherapy and / or combined chemotherapy.

[0005] 1. Surgical treatment. Surgery is the only curative treatment for pancreatic cancer, but the prognosis is very poor, and the median survival of patients after surgery is usually less than 20 months, and the 5-year survival rate is low. Surgical treatment is generally divided into radical surgery and palliative surgery, and radical surgery is divided into standard radical surgery and extended radical surgery. The main surgical methods for pancreatic cancer include pancreaticoduodenectomy, distal pancreatectomy, arterial resection and reconstruction, portal vein resection, pylorus-preserving pancreaticoduodenectomy, partial jejunectomy, partial gastrectomy, etc. The main difference between extended radical surgery and standard radical surgery is the range of lymph node dissection. Extended radical surgery extends the range of lymph node dissection through the peritoneal route after cleaning the conventional lymph node area. However, surgical treatment is only limited to early-stage patients. Moreover, the resection rate of pancreatic cancer radical surgery is low, and the long-term efficacy is also very poor. In recent years, extended surgical resection has been advocated, which has significantly increased the resection rate, but the postoperative survival rate is still low. Palliative surgery has become the main treatment for pancreatic cancer, but it cannot effectively prolong the survival of patients.

[0006] 2. Targeted therapy. In recent years, targeted therapy has become a safe and effective emerging treatment. Under the guidance of endoscopic ultrasound, radioactive particles are implanted into the tumor, which can treat malignant tumors without killing or damaging normal tissues. In addition, clinical research data shows that inhibition of the NF-κb signaling pathway can inhibit tumor proliferation and promote tumor cell apoptosis. Therefore, tumor inhibitors targeting NF-κb are also a hot topic in clinical treatment. Pancreatic cancer is not a single disease, and there are great differences in gene mutation spectrum and biological behavior between different patients, even within the same tumor. This means that drugs targeting a specific target (such as EGFR, KRAS) may only be effective for a small number of patients carrying that target. There is no high-frequency and key'main driver' target like EGFR in lung cancer.

[0007] 3. Chemotherapy. The current clinical chemotherapy methods generally include single-agent chemotherapy, combination chemotherapy, and new drug chemotherapy. In clinical practice, combination therapy is generally used. Neoadjuvant therapy, as a new treatment option, is being applied in clinical treatment, which refers to the use of systemic therapy before local surgery in malignant tumors. The overall efficacy is limited, and the survival period is not significantly prolonged: even the most effective standard chemotherapy regimen (such as FOLFIRINOX or AG regimen) can only extend the median survival of patients with advanced pancreatic cancer to a few months to about a year. The vast majority of patients will eventually progress. The response rate is not high: the sensitivity of pancreatic cancer to chemotherapy drugs is generally low. The response rate of single-agent gemcitabine is only about 10%. Even the more potent FOLFIRINOX regimen, the response rate is difficult to exceed 30%.

[0008] 4. Radiotherapy. Local recurrence is one of the main reasons for treatment failure in pancreatic cancer, 75% of patients have local recurrence, and the technology and quality of radiotherapy have been proven to be related to the treatment effect of patients. Stereotactic body radiotherapy (SBRT) is a special form of radiotherapy, which uses the progress of irradiation technology and image-guided technology to accurately implement low fractionation and high dose irradiation; It has been widely used in head and chest tumors; It has also been applied to body tumors such as pancreatic cancer. However, there are problems of positioning accuracy and organ movement: as the patient breathes, the pancreas moves up and down, making it difficult to accurately target the tumor. In order to ensure that the irradiation is not missed, it is often necessary to expand the irradiation range (planning target volume, PTV), thereby affecting more normal tissues. The "window" of radiation tolerance is narrow: to effectively kill pancreatic cancer cells, a very high radiation dose is required (usually >70 Gy). However, the surrounding normal tissues (especially the duodenum and stomach) are very sensitive to radiation, and their maximum tolerance dose is much lower than the dose required to kill the tumor.

[0009] 5. Immunotherapy. Immunotherapy has a significant effect on the treatment of solid tumors such as melanoma and lung cancer, and has become an important anti-tumor method after surgery and radiotherapy and chemotherapy. Vaccine therapy is a traditional immunotherapy. Tumor vaccine is one of the research hotspots in recent years. Its mechanism is to induce specific immune and humoral immune responses in the human body according to the patient's own immune system, using tumor cells or antigen components of malignant tumors, to improve the body's ability to prevent cancer and prevent the growth and metastasis of malignant tumors, in order to achieve the purpose of eliminating or controlling malignant tumors. Immune checkpoint inhibitors are the most commonly used specific immune modulators, which block two T cell inhibitory protein kinases, namely programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4). Passive immunization methods include antibody-directed therapy and adoptive immunotherapy, and the current clinical application of pancreatic cancer treatment is mainly adoptive immunotherapy. Tumor adoptive immunotherapy is to induce, activate and expand the precursors of anti-tumor effector cells in the body, and then transfer them to tumor patients to improve their anti-tumor immunity. There is a serious lack of T cell infiltration, and most pancreatic cancer tumors lack cytotoxic T cells that can recognize and kill cancer cells. This type of tumor is called "immune exempt" or "cold tumor", which is full of immune suppressor cells, such as myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), and M2-type tumor-associated macrophages (TAMs). These cells together create an "immunological desert" that actively suppresses and destroys any possible anti-tumor immune response.

[0010] STAT3 plays an important role in the occurrence, development and metastasis of tumors, and is currently recognized as an oncogene, and has become a hotspot in the field of tumor treatment research. Previous studies have found that STAT3 is continuously over-activated in pancreatic cancer, which is the 'key pivot' driving the malignant progression of pancreatic cancer. The continuous activation of the JAK2 / STAT3 pathway is the key to driving the malignant progression of pancreatic cancer. STAT3 is a proven and extremely attractive therapeutic target for pancreatic cancer, and its targeted therapy is considered to be a potential key to breaking the stalemate in the treatment of pancreatic cancer. Direct targeting of STAT3 is extremely attractive, but also faces many problems, such as targeting toxicity, narrow therapeutic window, drug delivery barrier and the like. SUMMARY

[0011] In view of the above technical problems, the purpose of the present application is to provide a new type of targeted inhibition drug, which belongs to a new type of azetidine compound, is a STAT3 targeted inhibitor, and can be directly used in the preparation of a drug for preventing and treating pancreatic cancer, thereby providing a new approach and technical idea for treating pancreatic cancer.

[0012] In order to achieve the above purpose, the technical scheme adopted by the present application is as follows: A new type of targeted inhibition drug, wherein the targeted inhibition drug comprises a main active ingredient azetidine compound. The molecular formula of the azetidine compound is C 28 H 22 O4N5SF5, and the molecular weight is 619.57. The structural formula is formula (I). The azetidine compound is obtained by halogen substitution reaction using compound A and compound B as starting materials, compound C is obtained by removing benzoyl group from compound C, and compound D is obtained by halogen substitution reaction again. The molecular formula of the compound A is C 10 H 12 NCl. The molecular formula of the compound B is C 22 H 27 O4N3Si. The molecular formula of the compound C is C 32 H 38 O4N4Si. The molecular formula of the compound D is C 24 H 32 O2N4Si.

[0013] The application of the new type of targeted inhibition drug in the preparation of a preparation for preventing and treating pancreatic cancer, wherein the new type of targeted inhibition drug is used alone. Or, The new type of targeted inhibitory drug is used in combination with other excipients.

[0014] As preferably, the purity of the main active ingredient azetidine compound is ≥98%.

[0015] As preferably, the targeted inhibitory drug is used in inhibiting tumor tissue growth, inhibiting tumor cell growth and reproduction, promoting STAT3 transfer to mitochondria and inhibiting mitochondrial complex enzyme activity.

[0016] As preferably, the tumor tissue growth includes tumor weight and tumor volume. The inhibition of tumor tissue growth includes reducing tumor weight and reducing tumor volume.

[0017] As preferably, the inhibition of tumor cell growth and reproduction is achieved by inhibiting tumor growth-related protein expression, and then inducing apoptosis of pancreatic cancer cells.

[0018] As preferably, the tumor growth-related protein includes c-Myc, Bcl-X, VEGF or Survivin protein in tumor cancer cells MIA Paca-2 and / or PANC-1.

[0019] As preferably, the promotion of STAT3 transfer to mitochondria is the increase of mitochondrial STAT3 transmembrane import by acting on GRIM-19.

[0020] As preferably, the mitochondrial complex enzyme includes complex I, complex III and complex IV.

[0021] Compared with the prior art, the present application has at least the following technical effects: The present application provides a new type of targeted inhibitory drug, which belongs to a new type of azetidine compound and is a STAT3 targeted inhibitor, which can be directly used in the preparation of drugs for preventing and treating pancreatic cancer, and provides a new way and technical idea for treating pancreatic cancer.

[0022] The application of the new type of targeted inhibitory drug in the preparation of drugs for preventing and treating pancreatic cancer shows that the compound can effectively inhibit the tumor growth state of nude mice pancreatic cancer, inhibit cell growth-related protein expression, inhibit mitochondrial complex enzyme activity and induce cell apoptosis, has a significant preventive and therapeutic effect on pancreatic cancer, and is expected to become a new drug for the research and development of pancreatic cancer treatment. BRIEF DESCRIPTION OF DRAWINGS

[0023] Figure 1 Figure 2 is a schematic diagram of the effect of H334 on the tumor volume of pancreatic cancer nude mice. Figure 2 Figure 9 is a diagram showing the effect of H334 on the weight of pancreatic cancer tumor in nude mice; Figure 3 Figure 10 is a diagram showing the effect of H334 on the expression of STAT3 downstream proteins; Figure 4 Figure 11 is a diagram showing the effect of MIA Paca-2 and PANC-1 on the activities of mitochondrial complex I, II, III and IV; Figure 5 Figure 12 is a diagram showing the effect of H334 on the interaction between STAT3 and GRIM-19; Figure 6 Figure 13 is a diagram showing the effect of H334 on the apoptosis of pancreatic cancer cells; Figure 7 Figure 14 is a diagram showing the reaction process of preparing H334; Figure 8 Figure 15 is a diagram showing the reaction process of the molecular formula of H334. DETAILED DESCRIPTION

[0024] In order to more clearly illustrate the technical solutions of the embodiments of the present application or the prior art, the present application will be briefly introduced below in combination with the drawings and the description of the embodiments or the prior art. Obviously, the following description of the drawings structure is only some embodiments of the present application, and for those skilled in the art, other drawings can also be obtained without creative labor. It should be noted that the description of these embodiments is used to help understand the present application, but does not constitute a limitation on the present application.

[0025] The technical solution of one specific embodiment of the present application is: The azetidine compound is obtained by halogen substitution reaction of compound A and compound B as starting materials to obtain compound C; compound C is obtained by removing the benzoyl group to obtain compound D; and compound D is obtained by halogen substitution reaction again. The molecular formula of the compound A is: C 10 H 12 NCl; The molecular formula of the compound B is: C 22 H 27 O4N3Si The molecular formula of the compound C is: C 32 H 38 O4N4Si The molecular formula of the compound D is: C 24 H 32 O2N4Si.

[0026] The azetidine compound (C 28 H22 The structural formula of the azetidine compound (hereinafter referred to as H334) is shown as formula (I): Formula (I) .

[0028] The reaction process and molecular formula of the azetidine compound (hereinafter referred to as H334) are shown as follows: Figure 7 and 8 .

[0029] Experimental Example: 1. Experimental materials 1.1 Drug H334 was provided by Professor Xu's research group in the Department of Pharmaceutical Chemistry, Institute of Pharmaceutical Research, Beijing Union Medical College. The purity was determined by HPLC to be ≥98%, and paclitaxel was purchased from Shanghai Kanglang Biotechnology Co., Ltd.

[0030] 1.2 Cells Human pancreatic cancer cells MIA PaCa-2 and PANC-1 were purchased from the Cell Center of the Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences. The culture conditions of the cells were 37°C, 5% CO2, and saturated humidity. Balb / c nude mice were purchased from Beijing Sibeifu Experimental Animal Technology Co., Ltd.

[0031] 2. Experimental methods 2.1 Pancreatic cancer ectopic transplantation in nude mice Under sterile conditions, human pancreatic cells MIA PaCa-2 were collected, and the cell density was adjusted to 5×10 7 / mL with sterile normal saline. 0.2 mL was inoculated subcutaneously in the axillary region of the nude mice. When the tumor grew to a size of 1 cm in diameter, it was removed under sterile conditions, cut into 1 mm×1 mm tumor pieces, and evenly inoculated subcutaneously in the axillary region of the nude mice. When the tumor volume approached 200-400 mm 3 , the mice were grouped and weighed, with 6 mice in each group. The formal experimental grouping method was as follows: the control group was given distilled water by gavage daily; the paclitaxel group was given 10 mg / kg by intraperitoneal injection every two days. The H334 20 mg / kg administration group was given intraperitoneal injection every two days. The administration period was about 27 days.

[0032] Results evaluation: body weight was measured twice a week, and the length and width of the tumor were measured with a vernier caliper. The tumor volume was calculated according to the formula V=a×b 2 / 2, where a was the length of the tumor and b was the width of the tumor. The nude mice were sacrificed by cervical dislocation and photographed, then the tumor tissue was removed and weighed, and finally the tumor inhibition rate was calculated. Part of the tumor tissue was fixed in 4% paraformaldehyde, and the other part was stored at -80°C.

[0033] 2.2 Western Blot for detecting protein expression changes Treated or untreated cultured cells MIA Paca-2, PANC-1 were collected and whole cell lysates were prepared with radioimmunoprecipitation assay (RIPA) buffer. Equal amounts of total protein were taken for sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and immunoblot analysis. The primary antibodies used included anti-c-Myc, Bcl-X, VEGF, Survivin and β-actin. Cells were seeded at a density of 1.4 x 10 4

[0034] 2.3 Enzymatic activity assay of respiratory chain complexes The activity of each complex (I (ab109721, Abeam), II (ab109908, Abeam), III (ab124537, Abeam) and IV (ab109909, Abeam)) was determined using the respective activity assay kit (colorimetric method). Mitochondria were lysed in the provided buffer to obtain a protein solution (5 pg / pL) and loaded into the provided plate before immunocapture. After washing away unbound proteins, the provided substrate and dye were added to each well and the absorbance was measured as instructed.

[0035] 2.4 Co-immunoprecipitation for detecting protein-protein interaction After cell collection, pre-cooled PBS was added for washing, and lysis buffer (containing protease inhibitors) was added for lysis on ice for 30 minutes. The supernatant was taken by centrifugation as the cell lysate. The lysate was mixed with the antibody specific to the target protein, and incubated at 4°C for 4 hours or overnight to form an antibody-target protein complex. Protein A / G magnetic beads were added and incubated at 4°C for 2 hours, and the magnetic beads captured the complex by binding to the Fc fragment of the antibody. The magnetic beads were washed with lysis buffer for 3-4 times to remove non-specifically bound proteins. SDS loading buffer was added to boil and dissociate the complex, and the supernatant was taken by centrifugation for SDS-PAGE electrophoresis. The interaction proteins were identified by Western blot.

[0036] 2.5 Flow cytometry for detecting apoptosis Logarithmic growth phase MIA Paca-2 cells were digested into a single cell suspension at a concentration of 1 x 10 5 ​Cells were added at a density of 2 mL / mL to 6-well plates. The next day, cells were treated with different concentrations of H334 for 48 h. Cells in the 6-well plates were then digested with 0.25% trypsin (without EDTA), and the digestion was terminated with supernatant culture medium. Cells were collected by centrifugation at 1000 rpm for 5 min at 4°C. Cells were washed with pre-chilled PBS, centrifuged again at 1000 rpm for 5 min at 4°C, and the cell pellet was collected. 100 μL of 1× Binding Buffer was added to resuspend the cells, followed by 5 μL of Annexin V-FITC. The mixture was incubated at room temperature in the dark for 15 min. 10 min before instrumentation, 5 μL of PI was added for staining, and 400 μL of 1× Binding Buffer was added for analysis.

[0037] 3. Statistical Analysis Results are expressed as mean ± standard deviation. SPSS statistical software was used to perform ANOVE analysis on the experimental data. p <0.05 indicates a statistically significant difference.

[0038] 4. Experimental Results Data: 4.1 Effect of H334 on the volume of pancreatic cancer tumors in nude mice like Figure 1 The diagram shown illustrates the comparison of tumor volume in each group of nude mice. Compared to the control group, *** p <0.001.

[0039] Figure 1 The results showed that on day 27 of modeling, the tumor volume in the control group nude mice was 2536±76 mm. 3 The tumor volume in nude mice in group H334 was 898±53 mm. 3 The tumor volume in nude mice in the paclitaxel group was 1107±45 mm. 3 .

[0040] The results showed that H334 could significantly inhibit the growth of pancreatic cancer tumor volume in nude mice. p < 0.001), and its effect is more pronounced than that of the positive control drug paclitaxel over time.

[0041] 4.2 Effect of H334 on tumor weight in nude mice with pancreatic cancer like Figure 2 The diagram shown illustrates the comparison of tumor weight in nude mice across different groups. Compared to the control group, *** p <0.001.

[0042] Depend on Figure 2 The results showed that the tumor weight of nude mice in the control group was 3.21±0.5g, the tumor weight of nude mice in the H334 group was 0.23±0.12g, and the tumor weight of nude mice in the paclitaxel group was 0.70±0.24g.

[0043] Tumor weight is a macroscopic indicator of pancreatic growth, and the results showed that H334 could inhibit the growth of pancreatic cancer tumors in nude mice. p <0.001).

[0044] 4.3 Effects of H334 on the growth of pancreatic cancer tumor cells like Figure 3 As shown, H334 affects the expression of downstream proteins of STAT3.

[0045] Depend on Figure 3 The results showed that with increasing concentration, H334 at a concentration of 10 μM significantly inhibited the expression of proteins such as c-Myc, Bcl-X, VEGF, and Survivin in pancreatic cancer cells MIA Paca-2 and PANC-1, suggesting that H334 can effectively inhibit the expression of tumor growth-related proteins, induce apoptosis in pancreatic cancer cells, and inhibit the growth and proliferation of pancreatic cancer cells.

[0046] 4.4 Effect of H334 on the enzyme activity of respiratory chain complexes like Figure 4 As shown, MIA Paca-2 and PANC-1 affect the activities of mitochondrial complex enzymes I, II, III and IV.

[0047] Depend on Figure 4 The results showed that, by measuring the activity of the oxidative respiratory chain complex, H334 treatment significantly reduced the enzyme activity of complexes I, III, and IV compared with the positive controls rotenone (Rot), antimycin A (Anti-A), and potassium cyanide (KCN), while the enzyme activity of complex II did not change significantly compared with the positive control 3-nitropropionic acid (3-Ni).

[0048] These data suggest that H334 can cause mitochondrial dysfunction and respiratory chain obstruction, and that STAT3 mitochondrial translocation may mediate this toxic effect.

[0049] 4.5 Effects of H334 on the interaction between STAT3 and GRIM-19—A study conducted by immunoprecipitation in isolates rich in mitochondrial membrane proteins Since GRIM-19 is a chaperone protein that recruits STAT3 into mitochondria, H334 may promote the translocation of STAT3 to mitochondria by acting on GRIM-19. To verify this possibility, an immunoprecipitation assay was first performed to assess the effect of H334 on the interaction between STAT3 and GRIM-19.

[0050] like Figure 5 As shown, this illustrates the effect of H334 on the interaction between STAT3 and GRIM-19.

[0051] Figure 5 The results showed that after pancreatic cancer cells were exposed to H334, the binding of STAT3 to GRIM-19 increased significantly, suggesting that H334 may increase the transmembrane introduction of mitochondrial STAT3 through GRIM-19.

[0052] 4.6 Effect of H334 on apoptosis of pancreatic cancer cells like Figure 6 As shown, H334 has an effect on apoptosis in pancreatic cancer cells.

[0053] Figure 6 The results showed that after 48 h of H334 treatment, in MIA Paca-2 cells, 1 μM and 5 μM H334 increased the percentage of apoptosis from 1.32±0.16 to 11.97±1.29 and 36.10±2.13, respectively, suggesting that H334 can significantly induce apoptosis in pancreatic cancer cells.

[0054] In summary, the results indicate that H334 can significantly inhibit the growth of pancreatic cancer tumor weight and volume; inhibit the expression of proteins such as c-Myc, Bcl-X, VEGF, and Survivin; increase the transmembrane introduction of mitochondrial STAT3 through GRIM-19; inhibit the activity of mitochondrial complex enzymes; and induce apoptosis, thereby exerting a therapeutic effect on pancreatic cancer.

[0055] Finally, it should be noted that the above description is merely a preferred embodiment of the present invention and is not intended to limit the scope of protection of the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A novel targeted inhibitory drug, characterized in that, The targeted inhibitory drug contains a nitrogen-containing heterocyclic butane compound as its main active ingredient; The molecular formula of the nitrogen-containing heterocyclic butane compounds is: C 28 H 22 O4N5SF5, molecular weight: 619.57; The structural formula is (I); The azacyclobutane compounds are obtained by using compounds A and B as starting materials, followed by a halogen substitution reaction to obtain compound C; compound C is then subjected to the removal of the pyrocarbonyl group to obtain compound D; compound D is then subjected to another halogen substitution reaction to obtain the final product. The molecular formula of compound A is: C 10 H 12 NCl; The molecular formula of compound B is: C 22 H 27 O4N3Si; The molecular formula of compound C is: C 32 H 38 O4N4Si; The molecular formula of compound D is: C 24 H 32 O2N4Si.

2. The application of the novel targeted inhibitory drug as described in claim 1 in the preparation of an agent for the prevention and treatment of pancreatic cancer, characterized in that, The novel targeted inhibitory drug can be used alone; or, The novel targeted inhibitory drug is used in combination with other excipients.

3. The application of the novel targeted inhibitory drug according to claim 2 in the preparation of agents for the prevention and treatment of pancreatic cancer, characterized in that, The purity of the main active ingredient, a nitrogen-containing heterocyclic butane compound, is ≥98%.

4. The application of the novel targeted inhibitory drug according to claim 2 in the preparation of agents for the prevention and treatment of pancreatic cancer, characterized in that, The application of the targeted inhibitory drug in inhibiting tumor tissue growth, inhibiting tumor cell growth and proliferation, promoting STAT3 transfer to mitochondria, and inhibiting mitochondrial complex enzyme activity.

5. The application of the novel targeted inhibitory drug according to claim 4 in the preparation of an agent for the prevention and treatment of pancreatic cancer, characterized in that, The tumor tissue growth includes tumor weight and tumor volume; The inhibition of tumor tissue growth includes reducing tumor weight and decreasing tumor volume.

6. The application of the novel targeted inhibitory drug according to claim 4 in the preparation of an agent for the prevention and treatment of pancreatic cancer, characterized in that, The inhibition of tumor cell growth and proliferation is achieved by suppressing the expression of tumor growth-related proteins, thereby inducing apoptosis in pancreatic cancer cells and thus inhibiting tumor cell growth and proliferation.

7. The application of the novel targeted inhibitory drug according to claim 6 in the preparation of an agent for the prevention and treatment of pancreatic cancer, characterized in that, The tumor growth-related proteins include c-Myc, Bcl-X, VEGF, or Survivin proteins in tumor cancer cells MIA Paca-2 and / or PANC-1.

8. The application of the novel targeted inhibitory drug according to claim 4 in the preparation of an agent for the prevention and treatment of pancreatic cancer, characterized in that, The promotion of STAT3 translocation to mitochondria is achieved by a targeted inhibitory drug that increases the transmembrane delivery of STAT3 to mitochondria by acting on GRIM-19.

9. The application of the novel targeted inhibitory drug according to claim 4 in the preparation of an agent for the prevention and treatment of pancreatic cancer, characterized in that, The mitochondrial complex enzymes include complex enzyme I, complex enzyme III, and complex enzyme IV.

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