CN117045801A - Combination of m6A RNA methylase inhibitors and immune checkpoint inhibitors for the treatment of tumors - Google Patents
Combination of m6A RNA methylase inhibitors and immune checkpoint inhibitors for the treatment of tumors Download PDFInfo
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- CN117045801A CN117045801A CN202310516010.XA CN202310516010A CN117045801A CN 117045801 A CN117045801 A CN 117045801A CN 202310516010 A CN202310516010 A CN 202310516010A CN 117045801 A CN117045801 A CN 117045801A
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Abstract
The invention belongs to the field of biological medicine, and relates to a m6ARNA methylase inhibitor and immune checkpoint inhibitor combined treatment of tumors. The combined treatment method provided by the invention is to combine a tumor immunotherapeutic agent and STM2457 or derivatives thereof to treat tumors including melanoma and ovarian cancer. The novel anti-tumor drug combination therapy found by the invention has great significance for drug development and clinical treatment of melanoma or ovarian cancer.
Description
Technical Field
The invention belongs to the field of biological medicine, and relates to a m6A RNA (ribonucleic acid) methylase inhibitor and immune checkpoint inhibitor combined treatment for tumors.
Background
To date, more than 170 post-transcriptional RNA modifications have been found in humans. Among them, N6 methyl adenosine (m 6A) is the most common modification in eukaryotic messenger RNAs (mrnas). m6A modified proteins include METTL3, METTL14, YTHDC1, YTHDF2, and the like. m6A modification plays a key role in regulating RNA processing, splicing, nucleation, translation and stability, which is critical for the development of various human diseases such as cancer. m6A modification is abnormal in various types of cancers and is correlated with patient prognosis. Abnormalities in m6A modification are closely related to the occurrence, development and resistance of malignant tumors. As an oncogene, the m6A modified protein promotes tumor progression by up-regulating oncogenes or down-regulating tumor suppressor genes.
Programmed cell death protein 1 (PD-1) plays an important role in suppressing immune responses and promoting self-tolerance, including modulating T cell activity, activating antigen-specific T cell apoptosis programs and inhibiting apoptosis of conventional T cells. PD-L1 is a transmembrane protein, is considered as a co-inhibitor of immune response, and can bind to PD-1 to reduce proliferation of PD-1 positive cells, inhibit cytokine secretion thereof and induce apoptosis. PD-L1 also plays an important role in the progression of various malignant tumors, inhibiting the recognition and killing of tumor cells by the immune system, and promoting tumor immune escape. Blocking the PD-1/PD-L1 interaction by monoclonal antibodies has had a tremendous impact on cancer treatment.
Melanoma is a malignant tumor that originates from melanocytes. As an invasive skin cancer, the incidence of melanoma is increasing worldwide. Many studies have investigated the relationship of tumor cells to tumor microenvironment. However, more than half of melanoma patients do not respond to immune checkpoint inhibitor treatment, which is closely related to the immunosuppressive microenvironment in which the tumor cells are located. Through the combination with other medicines, the tumor infiltration CD8+ T cell level and the CD8/Treg ratio in the tumor microenvironment are improved, the immune 'cold' tumor is changed into the 'hot' tumor, and the effective rate of tumor immunotherapy is improved, so that the method has important clinical significance.
Disclosure of Invention
In some embodiments, the present invention provides a composition comprising: an anti-tumor immunotherapeutic agent and STM2457 or a derivative thereof.
In some embodiments, the anti-tumor immunotherapeutic agent comprises an immune cell or one or more immune checkpoint inhibitors.
In some embodiments, the immune cell is selected from a T cell, macrophage and/or monocyte or T cell comprising an artificial T cell receptor.
In some embodiments, the T cells are selected from one or more of Natural Killer (NK) cells, cytotoxic T Lymphocytes (CTLs), and regulatory T cells.
In some embodiments, the T cell is selected from a T lymphocyte.
In some embodiments, the T cells are selected from T lymphocytes from cord blood sources.
In some embodiments, the immune checkpoint inhibitor comprises a polypeptide, a monoclonal antibody, or a chemically synthesized small molecule inhibitor.
In some embodiments, the immune checkpoint inhibitor comprises a PD-L1 inhibitor, a PD-1 inhibitor, and/or a CTLA-4 inhibitor.
In some embodiments, the PD-1 inhibitor is an antibody or antigen-binding fragment thereof.
In some embodiments, the PD-1 inhibitor is a PD-1 antibody.
In some embodiments, the anti-tumor immunotherapeutic agent comprises an antibody or antibody fragment that targets a tumor-specific antigen.
In some embodiments, the STM2457 has a structural formula shown in formula (I):
in some embodiments, the composition further comprises a pharmaceutically acceptable carrier, excipient, or stabilizer.
In some embodiments, the composition is an anti-tumor composition.
In some embodiments, the tumor comprises lung cancer (including squamous cell carcinoma, small-cell lung cancer, non-small cell lung cancer), gastrointestinal cancer, pancreatic cancer, glioblastoma, glioma, cervical cancer, ovarian cancer, liver cancer, hepatoma, bladder cancer, breast cancer, colon cancer, colorectal cancer, endometrial cancer, myeloma, multiple myeloma, salivary gland cancer, renal cell carcinoma, wilms' cell carcinoma, basal cell carcinoma, melanoma, prostate cancer, vulval cancer, thyroid cancer, testicular cancer, esophageal cancer, or a human single-cell leukemia cell.
In some embodiments, the inventors have discovered that PD-1 inhibitors (or PD-1 blockers) or T cells have very significant effects in combination with STM2457 in the treatment of melanoma and ovarian cancer, with the combination being far superior to the single administration.
In some embodiments, the combination will even produce a synergistic therapeutic effect beyond the expectations of those skilled in the art.
The combination of anti-CTLA-4 and anti-PD-1 therapies provides the potential for excellent efficacy, possibly due to each drug acting in a complementary or even synergistic manner. But combination therapy may result in greater toxicity. In previously untreated melanoma or recurrent small cell lung cancer patients, the incidence of drug-related grade 3-4 adverse events was 54% to 55%, while the incidence of blockade was 24% to 27%, whereas the incidence of ipp Li Shan antibody alone was 24% to 27%, and the incidence of Nivolumab alone was 15% to 16%. Therefore, the invention finds a new anti-tumor drug combination therapy, and has great significance for drug development and clinical treatment of melanoma.
In some embodiments, the present invention provides a kit comprising a first container, a second container, and a package insert; the first container comprises a medicament of an anti-tumor immunotherapeutic agent, the second container comprises a medicament of STM2457 or a derivative thereof, and the package insert comprises instructions for using the medicament to treat cancer in a subject.
In some embodiments, the anti-tumor immunotherapeutic agent comprises an immune cell or one or more immune checkpoint inhibitors.
In some embodiments, the immune cell is selected from a T cell, macrophage and/or monocyte or T cell comprising an artificial T cell receptor.
In some embodiments, the T cells are selected from one or more of Natural Killer (NK) cells, cytotoxic T Lymphocytes (CTLs), and regulatory T cells.
In some embodiments, the T cell is selected from a T lymphocyte.
In some embodiments, the T cells are selected from T lymphocytes from cord blood sources.
In some embodiments, the immune checkpoint inhibitor comprises a polypeptide, a monoclonal antibody, or a chemically synthesized small molecule inhibitor.
In some embodiments, the immune checkpoint inhibitor comprises a PD-L1 inhibitor, a PD-1 inhibitor, and/or a CTLA-4 inhibitor.
In some embodiments, the PD-1 inhibitor is an antibody or antigen-binding fragment thereof.
In some embodiments, the PD-1 inhibitor is a PD-1 antibody.
In some embodiments, the anti-tumor immunotherapeutic agent comprises an antibody or antibody fragment that targets a tumor-specific antigen.
In some embodiments, the STM2457 has a structural formula shown in formula (I):
in some embodiments, the invention provides the use of any of the compositions in the manufacture of a medicament for treating cancer.
In some embodiments, the cancer comprises lung cancer (including squamous cell carcinoma, small-cell lung cancer, non-small cell lung cancer), gastrointestinal cancer, pancreatic cancer, glioblastoma, glioma, cervical cancer, ovarian cancer, liver cancer, hepatoma, bladder cancer, breast cancer, colon cancer, colorectal cancer, endometrial cancer, myeloma, multiple myeloma, salivary gland cancer, renal cell carcinoma, wilms' cell carcinoma, basal cell carcinoma, melanoma, prostate cancer, vulval cancer, thyroid cancer, testicular cancer, esophageal cancer, or a human single-cell leukemia cell.
In some embodiments, the invention provides the use of STM2457 or a derivative thereof in the manufacture of a medicament for the treatment of melanoma or ovarian cancer.
In some embodiments, the STM2457 has a structural formula shown in formula (I):
drawings
The volume and mass measurements of the mouse tumors in the four sets of protocols shown in fig. 1 indicate that STM2457 and PD-1 antibodies used in combination effectively inhibit the growth of mouse melanoma. (fig. 1A) STM2457 and PD-1 antibody groups significantly reduced tumor weight relative to NC control groups in the four-group regimen. (fig. 1B) STM2457 and PD-1 antibody groups significantly reduced tumor volume relative to NC control groups in the four-group regimen.
The results of single cell CD45 flow analysis of mouse tumors in the four sets of protocols in fig. 2 indicate that the combination of STM2457 and PD-1 antibodies can effectively improve tumor microenvironment, i.e., increase the proportion of hematopoietic lineage cells in B16F0 tumors.
The result of the single cell sequencing data analysis of the tumor in FIG. 3 shows that the combination of STM2457 and PD-1 antibodies can effectively promote the mitosis of T cell population and the maintenance of the expression of related genes of stem cell population in B16F0 tumor.
FIG. 4 is a flow chart of the administration of STM2457 in combination with PD-1 antibodies.
Figure 5 shows the combination treatment of ovarian cancer with STM2457 and T cells. (FIG. 5A) A1847 cells (labeled red fluorescence) and T cells, and STM 2457. (fig. 5B) tumor cell death rate (%), STM2457 group vs nc+t group P <0.001 calculated for the number of a1847 cells detected by flow cytometry.
FIG. 6 is a comparison of the inhibition effect of the m6A methylase inhibitor STM2457 alone on different tumor cells.
Figure 7 shows the combination treatment of B16 melanoma with STM2457 and T cells. Tumor cell mortality (%) calculated for the number of B16 cells detected by flow cytometry, STM2457 group vs nc+t group P <0.001.
Detailed Description
The technical solution of the present invention is further illustrated by the following specific examples, which do not represent limitations on the scope of the present invention. Some insubstantial modifications and adaptations of the invention based on the inventive concept by others remain within the scope of the invention.
The beta-cyclodextrin solution used in the following examples was purchased from Aladin-e company (https:// www.aladdin-e.com /), under the designation H108813. The PD-1 antibody used was purchased from BioXcell company (https:// bXcell. Com) under the trade designation BE0146. The PBS buffer used was purchased from HyClone, cat# SH30028.02.
"comprising" or "including" is intended to mean that the compositions (e.g., media) and methods include the recited elements, but not exclude other elements. When used to define compositions and methods, "consisting essentially of … …" means excluding other elements that have any significance to the combination for the purpose. Thus, a composition consisting essentially of the elements defined herein does not exclude other materials or steps that do not materially affect the basic and novel characteristics of the claimed invention. "consisting of … …" means the process steps excluding trace elements and essential elements of other components. Embodiments defined by each of these transitional terms are within the scope of this invention.
The components of the "composition" herein may be present in a mixed form or may be packaged separately. The separately packaged components may also contain their respective adjuvants. The adjuvant refers to a means for assisting the curative effect of the medicine in pharmacy. In the case of separate packages for the components of the composition, the individual components of the separate packages may be administered simultaneously or in any order, wherein the patient is treated with one drug and then administered with the other. The patient refers to a mammalian subject, particularly a human.
The tumor immune therapy is a therapeutic method for controlling and eliminating tumor by restarting and maintaining tumor-immune circulation and restoring normal anti-tumor immune response of the body. "tumor immunotherapeutic" refers to a drug for "tumor immunotherapy" and includes monoclonal antibody immune checkpoint inhibitors, therapeutic antibodies, cancer vaccines, cell therapies, small molecule inhibitors, and the like.
Herein, STM refers to "STM2457".
Example 1
1. Drug configuration
(1) The preparation method of the m6A methylase inhibitor working solution comprises the following steps:
1) Dissolving beta-cyclodextrin in sterilized ultrapure water to obtain beta-cyclodextrin solution with the mass fraction of 20% (w/v), and filtering with a filter membrane with the mass fraction of 0.22 μm in a biosafety cabinet to ensure the sterility of the solution;
2) And (3) dissolving the STM2457 medicine in the beta-cyclodextrin solution in the step (1), and fully and uniformly shaking at 42 ℃ to form a homogeneous STM 2457-beta-cyclodextrin solution. STM2457 was found to have a final concentration of 6.25mg/mL.
(2) Immune checkpoint drug configuration method:
PD-1 antibodies were diluted to 2.5mg/mL using PBS buffer.
2. Evaluation of inhibition of growth of murine melanoma B16F0 Using STM2457 in combination with PD-1 antibody
Mouse melanoma B16F0 (or "B16") was inoculated into 6-8 week old C57BL/6J mice, each with 2X 10≡5 cells. After the tumor mass was reached, injections of different drug combinations (four groups, NC, STM2457, PD-1 antibody, STM2457+PD-1 antibody, respectively) were initiated and the mice were periodically examined for changes in body weight and tumor volume. The results showed that the STM2457+PD-1 antibody group had the most significant tumor growth inhibition effect (FIG. 1).
3. Evaluation of melanoma microenvironment changes Using STM2457 in combination with PD-1 antibodies
Taking tumor obtained by dissecting the above mice, cleaning with PBS, discarding necrotic tissue part, taking part of tumor into 1.5mL centrifuge tube, and cutting to 1mm 3 About the size of the pieces, 1.5mL of pre-warmed DMEM medium (containing 2mg/mL collagenase P,20ug/mL DNase I enzyme final concentration) was added. Digestion is carried out for 15min at 37 ℃, vibration is carried out, filtration is carried out by a 70um filter membrane, and supernatant is removed by centrifugation. 700ul of erythrocyte lysate is added into an EP tube, after 4 DEG lysis for 10min, equal volume of serum is added for termination, a single cell sample can be obtained, then FITC-CD45 antibody staining is carried out, and then flow cytometry analysis is carried out. The results show that the three groups of protocols (STM 2457, PD-1 antibody, STM2457+PD-1 antibody) increased the proportion of hematopoietic lineage cells compared to the NC control group, demonstrating that the combination of STM2457 and PD-1 antibodies effectively improves melanoma microenvironment (FIG. 2).
4. Evaluation of the Effect of STM2457 and PD-1 antibody combination on melanoma Global Gene expression
Taking the cell sample obtained in the step 3, and performing single cell transcriptome (scRNA-seq) analysis. Analysis of the data shows that the STM2457+PD-1 antibody set is effective in promoting T cell mitosis and stem cell population maintenance-related gene expression in the immune microenvironment in B16FO tumors relative to the PD-1 antibody set alone, indicating that STM2457 can enhance T cell activity and reduce T cell failure (FIG. 3).
Note that: the four groups in fig. 1-3 are:
(1) NC group (or nc+nc):
(2) Nc+pd1 group (or PD-1 antibody group):
(3) Stm+nc group (STM 2457 group):
(4) Stm+pd1 group (STM 2457& PD-1 antibody group):
STM injection at 50mg/kg, approximately 1.25 mg/mouse per mouse, once daily; the PD-1 antibody injection dose was 250 ug/dose, 2 times a week. The administration time was 2 weeks since the mice were subcutaneously vaccinated with the B16F0 tumor had a clear feeling of touch (after about 5-7 days). The flow chart is shown in fig. 4.
Example 2 evaluation of growth inhibition of ovarian cancer cells Using STM2457 in combination with T cells
At the cellular level, human ovarian cancer cells a1847 were treated with 1 μ M m6A methylase inhibitor STM2457 and then co-incubated with cord blood-derived T cells.
The method comprises the following specific steps: 1000A 1847 cells were seeded in 96-well plates, cultured for 3 days at a concentration of 1uM STM2457, cord blood-derived T cells of different combination schemes (wherein the number of T cells added was 1:1 in the ratio of the number of A1847 to the number of T cells) were added, four groups (NC; STM2457; NC+T; STM 2457+T) were added, and cells were harvested after 24 hours of incubation, and the number of A1847 cells was examined by flow cytometry to calculate the killing of tumor cells.
The results are shown in FIGS. 5A-5B. It can be seen that STM2457 in combination with T cells is effective in inhibiting the growth of ovarian cancer cells. Wherein, the T cell separation method of the umbilical cord blood source comprises the following steps:
separating mononuclear cells from umbilical cord blood by density gradient centrifugation, specifically, (1) diluting umbilical cord blood with PBS for 2 times, and centrifuging 750g in a clean sterile collecting tube at 25deg.C for 30min; (2) Transferring the MNC of the white middle layer into a new 50mL centrifuge tube; (3) centrifugation at 350g per tube +30mLPBS at 4deg.C for 10min; (4) Removing the supernatant, adding 5mL of erythrocyte lysate, incubating for 10min at 25 ℃, filling PBS (phosphate buffered saline) to dilute the erythrocyte lysate, and centrifuging for 10min at 4 ℃ at 300 g; (5) The cell pellet was resuspended in 25mLPBS, centrifuged at 300g for 10min at 4℃and repeated once more; (6) The cells were resuspended in PBS and counted to obtain cells as mononuclear cells. (7) Biotin-conjugated antibodies (CD 14, CD15, CD16, CD19, CD34, CD36, CD56, CD123, CD235 a) were added to the resuspended mononuclear cells for 5 minutes, followed by incubation with anti-biotin beads for 10 minutes, and the magnetically labeled cells were removed by magnetic column, thereby isolating high purity T lymphocytes.
Example 3 inhibition of different tumors by the m6A methylase inhibitor STM2457 alone
At the cellular level, murine melanoma cells B16 were treated with the 5 μ M m6A methylase inhibitor STM2457, respectively; human breast cancer cells MDA-MB-231 and MCF7; human mononuclear leukemia cells Thp1; mouse lung cancer cell LLC; human melanoma cells a375; human lung cancer cells H1299, H23, H460, H522 were treated.
The method comprises the following steps: 1000 cells were seeded in 96-well plates, treated with 5. Mu.M STM2457 for 4 days, incubated in an incubator for 1h after 10ul of CCK8 (Biyun days) was added to each well, and absorbance at 450nm was measured with an ELISA reader.
The results are shown in FIG. 6. THP-1 and MDA-MB-231 cells are sensitive to STM2457, and MCF7, LLC and H460 have about 20% inhibition effect, and the rest cancer cells are not sensitive.
EXAMPLE 4 evaluation of B16 melanoma cell growth inhibition Using STM2457 in combination with T cells
At the cellular level, murine melanoma cells B16 were treated with 1 μ M m6A methylase inhibitor STM2457 and then co-incubated with T cells from the spleen of the mice.
The method comprises the following specific steps: 1000B 16 cells are planted in a 96-well plate, after treatment culture for 3 days at the concentration of 1 mu M STM2457, spleen-derived T cells of mice with different combination schemes (wherein the number of the added T cells is added according to the ratio of the number of the B16 to the number of the T cells of 1:2) are added, four groups (NC, STM2457, NC+T and STM2457+T respectively) are added, the cells are collected after incubation for 24 hours, the number of the B16 cells is detected by using a flow cytometry, and the killing condition of tumor cells is calculated.
The results are shown in FIG. 7. It can be seen that STM2457 in combination with T cells is effective in inhibiting the growth of melanoma cells.
The method for separating the T cells from the spleen of the mouse comprises the following steps:
the spleen of the dissected mice is soaked in PBS, the spleen is reversely ground by a 1mL syringe, 1mL is filtered by a filter screen. Centrifuging 750g for 5min at 25 ℃ in a filtrate collecting pipe; (2) Removing the supernatant, adding 5mL of erythrocyte lysate, incubating for 10min at 25 ℃, filling PBS (phosphate buffered saline) to dilute the erythrocyte lysate, and centrifuging for 10min at 4 ℃ at 300 g; (5) The cell pellet was resuspended in 25mLPBS, centrifuged at 300g for 10min at 4℃and repeated once more; (6) The cells were resuspended in PBS and counted to obtain cells as mononuclear cells. (7) Biotin-conjugated antibodies (CD 11B, CD11c, CD19, CD45R (B220), CD49B (DX 5), CD105, MHC class II and Ter-119) were added to the resuspended mononuclear cells and incubated for 5min, followed by incubation with anti-biotin beads for 10min, and magnetically labeled cells were removed by magnetic column to isolate high purity T lymphocytes.
Claims (10)
1. A composition, wherein the composition comprises: an anti-tumor immunotherapeutic agent and STM2457 or a derivative thereof.
2. The composition of claim 1, wherein the anti-tumor immunotherapeutic agent comprises an immune cell or one or more immune checkpoint inhibitors.
Preferably, the immune cells are selected from T cells, macrophages and/or monocytes or T cells comprising artificial T cell receptors;
preferably, the T cells are selected from one or more of Natural Killer (NK) cells, cytotoxic T Lymphocytes (CTLs), and regulatory T cells;
preferably, the T cells are selected from T lymphocytes.
3. The composition of any one of claims 1-2, wherein the immune checkpoint inhibitor comprises a polypeptide, a monoclonal antibody, or a chemically synthesized small molecule inhibitor;
preferably, the immune checkpoint inhibitor comprises a PD-L1 inhibitor, a PD-1 inhibitor and/or a CTLA-4 inhibitor;
preferably, the PD-1 inhibitor is an antibody or antigen-binding fragment thereof;
preferably, the PD-1 inhibitor is a PD-1 antibody.
4. The composition of any one of claims 1-2, wherein the anti-tumor immunotherapeutic agent comprises an antibody or antibody fragment that targets a tumor-specific antigen.
5. A composition according to any one of claims 1 to 2, wherein the STM2457 has the structural formula shown in formula (I):
6. the composition of any one of claims 1-2, further comprising a pharmaceutically acceptable carrier, excipient, or stabilizer;
preferably, the composition is an anti-tumor composition;
preferably, the tumor comprises lung cancer, gastrointestinal cancer, pancreatic cancer, glioblastoma, glioma, cervical cancer, ovarian cancer, liver cancer, hepatoma, bladder cancer, breast cancer, colon cancer, colorectal cancer, endometrial cancer, myeloma, multiple myeloma, salivary gland cancer, renal cell carcinoma, nephroblastoma, basal cell carcinoma, melanoma, prostate cancer, vulval cancer, thyroid cancer, testicular cancer, esophageal cancer, or a human mononuclear leukemia cell;
preferably, the cancer comprises ovarian cancer or melanoma.
7. A kit comprising a first container, a second container, and a package insert; the first container comprises a medicament of an anti-tumor immunotherapeutic agent, the second container comprises a medicament of STM2457 or a derivative thereof, and the package insert comprises instructions for using the medicament to treat cancer in a subject.
8. The kit of claim 7, wherein the anti-tumor immunotherapeutic agent comprises an immune cell or one or more immune checkpoint inhibitors;
preferably, the immune cells are selected from T cells, macrophages and/or monocytes or T cells comprising artificial T cell receptors;
preferably, the T cells are selected from one or more of Natural Killer (NK) cells, cytotoxic T Lymphocytes (CTLs), and regulatory T cells;
preferably, the T cells are selected from T lymphocytes.
Preferably, the immune checkpoint inhibitor comprises a polypeptide, monoclonal antibody, or a chemically synthesized small molecule inhibitor;
preferably, the immune checkpoint inhibitor comprises a PD-L1 inhibitor, a PD-1 inhibitor and/or a CTLA-4 inhibitor;
preferably, the PD-1 inhibitor is an antibody or antigen-binding fragment thereof;
preferably, the PD-1 inhibitor is a PD-1 antibody.
Preferably, the anti-tumor immunotherapeutic agent comprises an antibody or antibody fragment that targets a tumor-specific antigen;
preferably, the structural formula of STM2457 is shown in formula (I):
9. use of a composition according to any one of claims 1-6 for the manufacture of a medicament for the treatment of cancer;
preferably, the cancer comprises lung cancer, gastrointestinal cancer, pancreatic cancer, glioblastoma, glioma, cervical cancer, ovarian cancer, liver cancer, hepatoma, bladder cancer, breast cancer, colon cancer, colorectal cancer, endometrial cancer, myeloma, multiple myeloma, salivary gland cancer, renal cell carcinoma, nephroblastoma, basal cell carcinoma, melanoma, prostate cancer, vulval cancer, thyroid cancer, testicular cancer, esophageal cancer, or a human mononuclear leukemia cell;
preferably, the cancer comprises ovarian cancer or melanoma.
Use of stm2457 or a derivative thereof in the manufacture of a medicament for the treatment of melanoma or ovarian cancer;
preferably, the structural formula of STM2457 is shown in formula (I):
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