Use of pyrithione derivative in treatment of colorectal cancer

Abstract

A use of a pyrithione derivative in the treatment of colorectal cancer demonstrates an affinity of zinc pyrithione (ZPT), copper pyrithione (CPT) and monomeric copper pyrithione (monomeric CPT) for epigenetic modifying enzyme HSPBAP1, wherein the pyrithione derivative can effectively target the HSPBAP1 protein; moreover, in vitro migration and invasion assays were performed on various colorectal cancer cell lines, revealing that ZPT, CPT, and monomeric CPT significantly inhibit in vitro migratory and invasive capabilities of various colorectal cancer cells, thereby indicating that the pyrithione derivative has broad anti-metastatic capabilities against colorectal cancer.

Description

Uses of pyrithione derivatives in the treatment of colorectal cancer

[0001] This application claims priority to Chinese Patent Application No. 202510201812.0, entitled "Use of Pyridinethione Derivatives in the Treatment of Colorectal Cancer", with a priority date of February 24, 2025. The applicant of the earlier application is Xiamen University. Technical Field

[0002] This application belongs to the field of biomedical technology, specifically relating to the use of pyridinethione derivatives in the treatment of colorectal cancer. Background Technology

[0003] Colorectal cancer (CRC) is the third most common type of cancer worldwide and the second leading cause of cancer death globally. According to the World Health Organization (WHO) recent global cancer statistics report, colorectal cancer accounts for 10% of all new cancer cases worldwide, ranking third after breast and lung cancer. It is a prevalent and deadly malignant tumor with a significant unmet need for treatment, and this need is growing.

[0004] Activation, invasion, and metastasis are hallmarks of cancer and the most prominent characteristics of malignant tumors. Currently, metastasis remains the leading cause of cancer death, accounting for over 90% of cancer patient deaths. Although EGFR inhibitors and immunotherapy for patients with DNA mismatch repair deficiencies are available, targeted therapies for most colorectal cancer metastases remain severely lacking. Metastasis is a cascade process that can be divided into three stages: dissemination, dormancy, and colonization. During this period, primary tumor cells acquire invasive migratory capabilities, becoming metastasis-initiating cells (MICs). MICs invade the bloodstream or lymphatic vessels and spread through the circulatory system, becoming circulating tumor cells (CTCs). During this spread, most CTCs are eliminated by physical, biochemical, oxidative, or immune stress; a small number of CTCs extravasate through capillaries and invade distant organs, becoming disseminated tumor cells (DTCs).

[0005] Most disseminated intracellular tumors (DTCs) can be cleared by organ-specific or systemic immune defenses. A small number of DTCs can evade immune surveillance by entering a dormant state, subsequently entering a proliferative state to form micrometastasis and macrometastasis. Each step in the metastasis cascade requires metastatic cells to acquire a large number of characteristics, and epigenetic regulation plays a crucial role in this process. Currently, numerous studies have revealed that various gene expression programs and epigenetic regulatory mechanisms are involved in the metastasis cascade, including DNA methylation, histone modification, 3D chromatin organization, and non-coding RNA. These mechanisms can reshape cellular phenotypic characteristics by regulating gene expression without altering the genomic DNA sequence.

[0006] Zinc pyrithione (ZPT) is a drug approved by the US Food and Drug Administration (FDA) as a topical antibacterial agent for the treatment of dandruff caused by Malassezia. It has a long history of safe and effective use and also shows some therapeutic potential for prostate cancer, acute myeloid leukemia, oral cancer, lung cancer, liver cancer, ovarian cancer, melanoma, and triple-negative breast cancer. However, the effects of ZPT and its derivatives on colorectal cancer are currently unknown. Summary of the Invention

[0007] This application provides the use of pyridinethione derivatives in the treatment of colorectal cancer, wherein the pyridinethione derivatives can target the epigenetic modifying enzyme HSPBAP1 and inhibit colorectal cancer migration and invasion.

[0008] This application provides the use of pyridinethione derivatives in the preparation of drugs for treating colorectal cancer, wherein the structure of the pyridinethione derivative is shown in Formula I, and R in Formula I is selected from any of the following: Zn + Cu + and R1 includes Zn 2+ or Cu 2+ ;

[0009] In a preferred embodiment of this application, the therapeutic effect of the colorectal cancer treatment drug includes targeting the epigenetic modifying enzyme HSPBAP1 with the pyridinethione derivative to inhibit colorectal cancer migration and / or invasion.

[0010] In a preferred embodiment of this application, the effective concentration of the pyridinethione derivative in the colorectal cancer treatment drug is not less than 5 μM.

[0011] In a preferred embodiment of this application, the pyridinethione derivative includes any one of the following:

[0012] This application also provides the use of pyridinethione derivatives in the preparation of epigenetic enzyme HSPBAP1 targeted agents, the structure of which is shown in Formula I.

[0013] In a preferred embodiment of this application, the effective concentration of the pyridinethione derivative in the epigenetic enzyme HSPBAP1 targeting agent is not less than 5 μM.

[0014] In a preferred embodiment of this application, the pyridinethione derivative includes any one of the following:

[0015] This application also provides a targeted agent for the epigenetic modifying enzyme HSPBAP1, comprising a pyridinethione derivative as the active ingredient and pharmaceutically acceptable excipients; the structure of the pyridinethione derivative is shown in Formula I.

[0016] This application also provides a drug for inhibiting the migration and invasion of colorectal cancer, comprising a pyridinethione derivative as the active ingredient, and pharmaceutically acceptable excipients;

[0017] The structure of the pyridinethione derivative is shown in Formula I.

[0018] In a preferred embodiment of this application, the colorectal cancer includes colorectal cancer cell lines DLD1, HCT116, and SW480.

[0019] Beneficial effects: This application provides the pyridinethione derivatives shown in Figure 1, and specifically verifies the affinity of zinc pyridinethione (ZPT), copper pyridinethione (CPT), and copper pyridinethione monomer (CPT monomer) for the epigenetic modifying enzyme HSPBAP1. Based on fluorescence titration, the in vitro dissociation constant KD value of ZPT and HSPBAP1 protein was found to be 3.28 μM, indicating that ZPT can effectively target HSPBAP1 protein. At the same time, the in vitro migration and invasion abilities of various colorectal cancer cell lines were measured, and it was found that 5 μM or 10 μM of ZPT, CPT, and CPT monomer can significantly inhibit the in vitro migration and invasion abilities of various colorectal cancer cells, indicating that the pyridinethione derivatives have broad anti-tumor metastasis ability against colorectal cancer. Attached Figure Description

[0020] Figure 1 shows the structure of zinc pyrithione (ZPT);

[0021] Figure 2 shows the structure of pyridinethione (PT);

[0022] Figure 3 shows the structure of copper pyrithione (CPT);

[0023] Figure 4 shows the structure of copper pyridinethione monomer (CPT monomer);

[0024] Figure 5 shows the results of the fluorescence titration experiment of ZPT and HSPBAP1 protein;

[0025] Figure 6 shows the results of ZPT inhibiting the migration and invasion of DLD1 cells;

[0026] Figure 7 shows the results of PT failing to inhibit the migration and invasion of DLD1 cells;

[0027] Figure 8 shows the results of CPT inhibiting the migration and invasion of DLD1 cells;

[0028] Figure 9 shows the results of CPT monomer inhibiting the migration and invasion of DLD1 cells;

[0029] Figure 10 shows the results of ZPT inhibiting the migration and invasion of HCT116 cells;

[0030] Figure 11 shows the results of ZPT inhibiting the migration and invasion of SW480 cells. Detailed Implementation

[0031] This application provides the use of pyridinethione derivatives in the preparation of drugs for treating colorectal cancer, wherein the structure of the pyridinethione derivative is shown in Formula I, and R in Formula I is selected from any of the following: Zn + Cu + and R1 includes Zn 2+ or Cu 2+ ;

[0032] The structural formula of the pyrithione derivative described in this application is shown in Figure 1, including zinc pyrithione (ZPT) as shown in Figure 1, CAS number 13463-41-7, molecular formula C 10 H8N2O2S2Zn, molecular weight 317.69, as shown in Figure 3, copper pyridinethione (bis(1-hydroxy-1h-pyridine-2-thionato-o,s)copper, CPT), CAS number 14915-37-8, molecular formula C 10H8CuN2O2S2, molecular weight 315.86; As shown in Figure 4, copper pyrithione (CPT monomer) is a 1:1 complex formed by one copper atom and one pyrithione atom, CAS number 154592-20-8, molecular formula C5H5CuNOS, molecular weight 189.70. This application also includes a comparative example using pyrithione (PT) as shown in Figure 2, CAS number 1121-30-8, molecular formula C5H5NOS, molecular weight 127.16. The results show that, except for PT, ZPT, CPT, and CPT monomer can effectively inhibit the migration and invasion of colorectal cancer cells.

[0033] This application does not specifically limit the source of PT, CPT, CPT monomer and ZPT. In the embodiments, they are all purchased from MedChemExpress (MCE) Company, with ZPT part number HY-B0572, PT part number HY-B1747, CPT part number HY-W140346 and CPT monomer part number HY-W152501.

[0034] In a preferred embodiment of this application, the effective concentration of the pyridinethione derivative in the colorectal cancer treatment drug is not less than 5 μM, such as 5 μM or 10 μM.

[0035] This application also provides the use of pyridinethione derivatives in the preparation of epigenetic enzyme HSPBAP1 targeted agents, the structure of which is shown in Formula I.

[0036] In this embodiment of the application, a fluorescence titration experiment was carried out to determine the dissociation constant of ZPT and its solvent DMSO with HSPBAP1 protein. The results showed that the KD value of ZPT with HSPBAP1 protein was 3.28 μM, indicating that ZPT can strongly bind to HSPBAP1.

[0037] This application also provides a targeted agent for the epigenetic modifying enzyme HSPBAP1, comprising a pyridinethione derivative as the active ingredient and pharmaceutically acceptable excipients; the structure of the pyridinethione derivative is shown in Formula I.

[0038] This application also provides a drug for inhibiting the migration and invasion of colorectal cancer, comprising a pyridinethione derivative as the active ingredient, and pharmaceutically acceptable excipients;

[0039] The structure of the pyridinethione derivative is shown in Formula I.

[0040] In a preferred embodiment of this application, the colorectal cancer includes colorectal cancer cell lines DLD1, HCT116, and SW480.

[0041] To further illustrate this application, the use of the pyridinethione derivatives provided in this application in the treatment of colorectal cancer is described in detail below with reference to the embodiments, but these should not be construed as limiting the scope of protection of this application.

[0042] Example 1

[0043] I. Construction and purification of prokaryotic expression vector for epigenetic modifying enzyme HSPBAP1

[0044] 1. Using the UCSC Genome Browser, the human gene HSPBAP1 was located based on the GRCh38 / hg38 genome. The full-length sequence encoding the HSPBAP1 protein (amino acids 1-461) was determined using the mRNA transcript from the NCBI reference sequence NM_001320728.2. Amino acids 1-260 of the human HSPBAP1 protein constitute the catalytic region of histone demethylases, and its encoded DNA sequence is shown in SEQ ID No. 1.

[0045] 2. This application specifically amplifies the nucleotide sequence shown in SEQ ID No. 1 from a human cDNA library using PCR. The 5' ends of the primers contain homologous sequences of the pGEX-4T1 vector multiple cloning site, namely the BamH1 and Xho1 restriction sites, respectively. The specific PCR primer sequences are as follows:

[0046] F (SEQ ID No. 2): 5'-GTTCCGCGTGGATCCGCAGCAGGCTCCGAGGCGACC-3';

[0047] R (SEQ ID No. 3): 5'-ATGCGGCCGCTCGAGGGTGATTGCCTCTTCTACCCG-3'.

[0048] PCR amplification system (25 μL): 5×PrimeSTAR Buffer (Mg 2+ 5 μL of Takara (plus), 2 μL of dNTP Mixture (Takara), 0.5 μL of primer F (10 mM), 0.5 μL of primer R (10 mM), 200 ng of cDNA, 0.5 μL of PrimeSTAR HSDNA Polymerase (2.5 U / μl) (Takara), and the remainder water.

[0049] PCR program: 98℃ for 5 min; 98℃ for 10 s, 56℃ for 30 s, 72℃ for 3 min, 30 cycles; 72℃ for 10 min; store at 4℃.

[0050] After the PCR procedure, the PCR products were separated by agarose gel electrophoresis. Fragments of approximately 1.5 kb in size were identified under UV light, excised from the gel, and recovered. The recovered DNA fragments were then eluted with 20 μL of ultrapure water for subsequent molecular cloning ligation reactions.

[0051] 3. This application uses a ligation-independent molecular cloning (LIC) method to ligate the PCR product into the pGEX-4T1 vector to obtain the plasmid pGEX-4T1-HSPBAP1(1-260), which can express the GST tag HSPBAP1(1-260) truncated somatic protein in large quantities in Escherichia coli.

[0052] Enzyme digestion system: 1 μL of (NEB), 2 μg of pGEX-4T1 plasmid, 1 μL of BamHI (NEB) and 1 μL of Xhol I (NEB);

[0053] After 7 hours of complete enzyme digestion, DNA gel was run. The digested vector fragment was located under UV light, the gel was cut, and the DNA fragment was recovered. The recovered DNA fragment was eluted with 20 μL of ultrapure water and used as a vector for subsequent ligation reactions.

[0054] Ligation system: 1 μL of 10X Exonuclease III Buffer (Takara), 3 μL of PCR product DNA, and 3 μL of enzyme-digested vector DNA.

[0055] Add ultrapure polymerase to a total volume of 9 μL, incubate on ice for 5 min, add 1 μL of Exonuclease III enzyme (200 U / μL, Takara), mix well, incubate on ice for 1 hour, then add 0.5 μL of 0.5 M EDTA (pH 8.0) to stop the reaction, and inactivate the exonuclease activity by incubating in a 60°C water bath for 5 min. After incubating on ice for 5 min, add the LIC product to 100 μL of competent cells of E. coli Turbo strain, incubate on ice for 30 min, heat shock in a 42°C water bath for 45 sec, and evenly spread the competent cells on bacterial agar plates containing ampicillin using the dilution plating method, and incubate overnight at 37°C. The next day, single colonies formed after successful transformation were picked, cultured in liquid bacterial culture medium containing ampicillin, and then plasmids were extracted and sent for plasmid DNA sequencing. The target plasmid pGEX-4T1-HSPBAP1(1-260) with the correct insertion of the target fragment was obtained.

[0056] 4. Next, the prokaryotic expression plasmid pGEX-4T1-HSPBAP1(1-260) was transformed into competent BL21 Rosetta™ strain (Novagen) cells of *E. coli*. The Rosetta™ strain supplements *E. coli* with six rare tRNAs, enabling universal translation. This facilitates the translation of longer coding sequences by GST-HSPBAP1(1-260), avoiding truncated fragmentation caused by premature translation termination due to insufficient tRNA, and promoting full-length expression of the fusion protein. The GST-tagged HSPBAP1(1-260) protein was purified according to the Glutathione Agarose (Thermo) product instructions. Specific bacterial transformation and purification methods are as follows:

[0057] (1) Transformation

[0058] ① 0.5 μL of plasmid pGEX-4T1-HSPBAP1(1-260) was transferred into 50 μL of Rosetta and incubated on ice for 30 min;

[0059] ②42℃ water bath heat shock for 60s;

[0060] ③Ice bath for 5 minutes immediately;

[0061] ④ Streak the medium onto a preheated LB solid medium plate containing ampicillin resistance.

[0062] ⑤ Invert the container and incubate overnight in a 37°C incubator.

[0063] (2) Induction

[0064] ① Small-scale culture. Add 20 mL of LB liquid medium to a 50 mL centrifuge tube, then add ampicillin to a final concentration of 1 mM. Pick a single colony and transfer it to a 50 mL centrifuge tube. Incubate in a shaker at 220 rpm and 37 °C for 8 h.

[0065] ② Expand the culture. Add 1 L LB liquid medium to a 2 L Erlenmeyer flask, then add ampicillin to a final concentration of 1 mM. Transfer 20 mL of bacterial culture to 1 L LB liquid medium and continue to culture in a shaker at 220 rpm and 37 °C for 3-4 h until the OD value is 0.7-0.8. Then add IPTG to a final concentration of 1 mM and culture in a shaker at 100 rpm and 25 °C overnight (12 h).

[0066] (3) Purification

[0067] ① Collect the bacteria. Centrifuge the bacterial culture at 4500 rpm for 15 min and discard the supernatant.

[0068] ② Resuspension and lysis. The bacterial cells were resuspended in 40 mL of PBS buffer. 40 mg of lysozyme (1 mg / mL) was dissolved in 2 mL of PBS + 1% Triton-X100 buffer and added to the resuspended bacterial solution. The solution was incubated on ice for 30 min, with gentle shaking three times during the incubation period. Then, 10% Triton-X100 was added to a final concentration of 1% Triton-X100. The bacterial solution was sonicated for 15 min using an ultrasonic cell disruptor at 10 s on / 15 s off and 80% concentration.

[0069] ③ Centrifugation incubation. After sonication, the bacterial culture is centrifuged at 13000-15000 rpm and 4℃ for 30 min. The supernatant is transferred to a new 50 mL centrifuge tube. 500 μL of 50% glutathione agarose beads is centrifuged at 700 G and 4℃ for 2 min. The supernatant is discarded. The mixture is then resuspended in 1 mL PBS + 1% Triton-X100 buffer, mixed, and centrifuged at 700 G and 4℃ for 2 min. The supernatant is discarded. This process is repeated 3 times. The mixture is then transferred to a 50 mL centrifuge tube and incubated at 4℃ for 4 h.

[0070] ④ Centrifugation and elution. After incubation, centrifuge at 1000G, 4℃ for 5 min, discard the supernatant and retain the agarose beads. Add 1 mL PBS + 1% Triton-X100 buffer to resuspend and mix well, then transfer to a 1.5 mL EP tube and centrifuge at 700G, 4℃ for 2 min. Discard the supernatant and repeat 4 times. Then resuspend with 1 mL PBS buffer, mix well, centrifuge at 700G, 4℃ for 2 min, discard the supernatant, and repeat 2 times. Add 1 mL 50 mM Tris-HCl (pH 8.0) / 10 mM reduced glutathione elution buffer and incubate for 10 min. Then transfer to the elution column and elute the target protein into a 1.5 mL EP tube.

[0071] II. In vitro affinity determination of ZPT and HSPBAP1 enzyme

[0072] The in vitro affinity of ZPT for HSPBAP1 protein was determined using a fluorescence quenching method. Specifically:

[0073] GST-tagged HSPBAP1(1-260) protein, eluted and purified in vitro, was used in a 50 mM Tris-HCl (pH 8.0) / 10 mM reduced glutathione solution for fluorescence quenching experiments. The HSPBAP1 protein was incubated with ZPT at increasingly higher concentrations at 25°C, followed by detection using a Varian Cary Eclipse fluorescence spectrophotometer. The dissociation constant was determined by quantitatively fitting the spectrum of ZPT-induced protein fluorescence quenching.

[0074] Using a 300 μL quartz cuvette, 200 μL of HSPBAP1(1-260) protein solution (protein concentration 5 μM) was added each time. The compound was diluted in DMSO to prepare a 10 mM stock solution. Taking ZPT as an example, with a molecular weight of 317.69 g / mol, 1 mg of ZPT was dissolved in 314.4 μL of DMSO to prepare a 10 mM ZPT stock solution. Subsequently, the 10 mM stock solution was diluted with 50 mM Tris-HCl (pH 8.0) to a 200 μM solution. After the protein solution and compound solution were equilibrated at room temperature for 30 minutes, the fluorescence spectrum of the protein solution was measured. Quantitative fluorescence was performed using a Varian Cary Eclipse fluorescence spectrophotometer in Scan mode, with the excitation wavelength set to 280 nm, the slit width set to 10 nm, and the emission spectrum scanned from 290 to 450 nm. Each sample was measured three times. Subsequently, titrations were initiated, with 2 μL of the compound solution added to 200 μL of the protein solution each time (approximately a 100-fold dilution). After the initial addition, the compound concentration in the system was 2 μM. After mixing by blow-pipette, the fluorescence spectrum was measured. The compound was then added to the protein solution in the same manner, gradually obtaining titration systems (0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30 μM, for a total of 15 additions). Using Graphpad Prism software, the area under the curve (AUC) of the protein-compound solution in the 290–450 nm range was obtained, and the change in AUC relative to the control sample at each titration concentration, i.e., ΔAUC, was calculated. After nonlinear fitting with the one-site-total option, the dissociation constant between the compound and the protein was finally obtained.

[0075] The dissociation constants of ZPT and its solvent DMSO with HSPBAP1 protein are shown in Figure 5. The KD value of ZPT with HSPBAP1 protein is 3.28 μM, indicating that ZPT can strongly bind to HSPBAP1 protein.

[0076] III. Cell migration experiment:

[0077] Three common colorectal cancer cell lines, DLD1, HCT116, and SW480, were cultured in a 37°C cell culture incubator with 5% CO2. Among them:

[0078] DLD1 cells were cultured in RPMI 1640 medium (BioInd, 01-100-1ACS) containing 10% fetal bovine serum (FBS) (BioInd, 04-001-1A);

[0079] HCT116 and SW480 were cultured in DMEM medium (BioInd, 01-052-1ACS) containing 10% FBS (BioInd, 04-001-1A).

[0080] Cells were digested with 0.25% trypsin (BioInd, 03-050-1A) and resuspended in the appropriate culture medium containing 0.5% FBS. After cell counting, cells were seeded at 200 μL per 8 μm well in cell culture chambers (NEST, 725301). The optimal concentrations were 50,000 DLD1 cells / chamber, 100,000 HCT116 cells / chamber, and 100,000 SW480 cells / chamber. For ZPT and its derivatives, ZPT and its derivatives were diluted to a final concentration of 5 or 10 μM and added to the upper chamber of the cell culture chamber. The chambers used for experiments were then placed in the center of a 24-well plate, and 600 μL of the appropriate culture medium containing 20% ​​FBS was added to the corresponding wells in the lower layer of the 24-well plate. PBS was added to the edge wells of the 24-well cell culture plate to prevent evaporation of the culture medium from the experimental chambers due to prolonged culture. After a certain culture time, the cells were collected, and the number of cells that passed through the pore size of the chamber was measured. Specifically, DLD1 cells were cultured for 24 hours, HCT116 cells for 60 hours, and SW480 cells for 48 hours.

[0081] After completing the above culture, remove the cell culture plate and gently remove the cells from the upper layer of the cell culture chamber with a cotton swab. Then, discard the culture medium and wash the upper and lower chambers with 200 and 500 μL of PBS, respectively, followed by 200 and 500 μL of 4% paraformaldehyde. After fixing at room temperature for 10 minutes, discard the paraformaldehyde solution. Add 200 and 500 μL of 0.15% crystal violet solution to the upper and lower chambers, respectively, and stain at room temperature for 20 minutes. After staining, rinse the chambers three times with tap water, and then place the wells and the plate in a ventilated area to air dry. Finally, examine each sample in three fields of view using an inverted microscope with a 10x objective lens, and count the number of cells that have migrated (or invaded) across the membrane using ImageJ software.

[0082] IV. Cell invasion experiment:

[0083] The substrate gel (BD, 356234) was placed overnight at 4°C. The next day, the substrate gel was diluted 1:10 with the appropriate culture medium. 50 μL of the diluted substrate gel was added to each cell culture chamber and incubated at 37°C for 1 hour. Subsequently, cell seeding, drug administration, staining, and quantification were performed as in the cell migration experiment above.

[0084] As shown in Figure 6, treatment of DLD1 cells with 5 or 10 μM ZPT for 24 hours significantly inhibited DLD1 cell migration and invasion. As shown in Figure 7, treatment of DLD1 cells with 5 or 10 μM PT for 24 hours failed to inhibit DLD1 cell migration and invasion. As shown in Figure 8, treatment of DLD1 cells with 5 or 10 μM CPT for 24 hours significantly inhibited DLD1 cell migration and invasion. As shown in Figure 9, treatment of DLD1 cells with 5 or 10 μM CPT monomer for 24 hours significantly inhibited DLD1 cell migration and invasion. As shown in Figure 10, treatment of HCT116 cells with 5 or 10 μM ZPT for 60 hours significantly inhibited HCT116 cell migration and invasion. As shown in Figure 11, treatment of SW480 cells with 5 or 10 μM ZPT for 48 hours significantly inhibited SW480 cell migration and invasion.

[0085] In summary, ZPT can inhibit the migration and invasion of DLD1 cells, HCT116 cells and SW480 cells, CPT and CPT monomers can inhibit the migration and invasion of DLD1 cells, and metal ion-free PT cannot inhibit the migration and invasion of DLD1 cells.

[0086] Although the above embodiments have provided a detailed description of this application, they are only some embodiments of this application, not all embodiments. People can obtain other embodiments based on these embodiments without creative effort, and these embodiments all fall within the protection scope of this application.

Claims

1. The application of pyridinethione derivatives in the preparation of drugs for treating colorectal cancer, characterized in that, The structure of the pyridinethione derivative is shown in Formula I, and R in Formula I is selected from any of the following: Zn + Cu + or R1 includes Zn 2+ or Cu 2+ ; 2. The application according to claim 1, characterized in that, The therapeutic effects of the drug for treating colorectal cancer include targeting the epigenetic modifying enzyme HSPBAP1 with the pyridinethione derivative to inhibit colorectal cancer migration and / or invasion.

3. The application according to claim 2, characterized in that, The colorectal cancer cells include DLD1 cells, HCT116 cells, and SW480 cells.

4. The application according to claim 1 or 2, characterized in that, The effective concentration of the pyridinethione derivative in the drug for treating colorectal cancer is not less than 5 μM.

5. The application according to claim 4, characterized in that, The pyridinethione derivative includes any one of the following:

6. The application according to claim 5, characterized in that, The pyridinethione derivative Inhibits the migration and invasion of DLD1 cells, HCT116 cells and SW480 cells; The pyridinethione derivative Inhibits the migration and invasion of DLD1 cells.

7. A drug for treating colorectal cancer, characterized in that, This includes active ingredients such as pyridinethione derivatives, as well as pharmaceutically acceptable excipients; The structure of the pyridinethione derivative is shown in Formula I, and R in Formula I is selected from any of the following: Zn + Cu + and R1 includes Zn 2+ or Cu 2+ ; 8. The application of pyridinethione derivatives in the preparation of epigenetic enzyme HSPBAP1-targeting agents, characterized in that, The structure of the pyridinethione derivative is shown in Formula I, and R in Formula I is selected from any of the following: Zn + Cu + or R1 includes Zn 2+ or Cu 2+ ; 9. The application according to claim 8, characterized in that, The effective concentration of the pyridinethione derivative in the epigenetic enzyme HSPBAP1 targeting agent is not less than 5 μM.

10. The application according to claim 9, characterized in that, The pyridinethione derivative includes any one of the following:

11. A drug targeting the epigenetic modifying enzyme HSPBAP1, characterized in that, This includes active ingredients such as pyridinethione derivatives, as well as pharmaceutically acceptable excipients; The structure of the pyridinethione derivative is shown in Formula I, and R in Formula I is selected from any of the following: Zn + Cu + and R1 includes Zn 2+ or Cu 2+ ; 12. A drug for inhibiting the migration and invasion of colorectal cancer, characterized in that, This includes active ingredients such as pyridinethione derivatives, as well as pharmaceutically acceptable excipients; The structure of the pyridinethione derivative is shown in Formula I, and R in Formula I is selected from any of the following: Zn + Cu + and R1 includes Zn 2+ or Cu 2+ ; 13. The medicament according to claim 12, characterized in that, The colorectal cancers mentioned include colorectal cancer cell lines DLD1, HCT116, and SW480.

14. A method for treating colorectal cancer using pyridinethione derivatives, characterized in that, The structure of the pyridinethione derivative is shown in Formula I, and R in Formula I is selected from any of the following: Zn + Cu + and R1 includes Zn 2+ or Cu 2+ ;

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