WO2024108676A1

WO2024108676A1 - Drug target for inhibiting tumor, use thereof, and oral drug

Info

Publication number: WO2024108676A1
Application number: PCT/CN2022/138169
Authority: WO
Inventors: 张弓; 陈洋; 余卓
Original assignee: 深圳承启生物科技有限公司
Priority date: 2022-11-21
Filing date: 2022-12-09
Publication date: 2024-05-30
Also published as: AU2022472191A1; CN115737619A

Abstract

The present invention relates to the field of targeted drug development and particularly to a drug target for inhibiting a tumor and use thereof. Specifically, provided is a drug target for inhibiting a tumor. The drug target is an eukaryotic initiation factor EIF2. Also provided are use of the drug target for inhibiting a tumor and an oral drug. By inhibiting the translation initiation factor EIF2 to inhibit eukaryotic translation initiation, the malignant phenotype effect of cancer cells can be safely suppressed, such that at least the following safety is realized: 1. different from other common translation initiation inhibitors (such as CHX and HTT), targeted inhibition of the EIF2 does not occupy the ribosome resource and relates to competitive binding of ribosome; 2. no ISR occurs in cells, toxic and side effects on normal cells can be reduced, and the drug can be safely taken orally.

Description

Drug target, use and oral drug for inhibiting tumor

Technical Field

The present application relates to the field of targeted drug development, and in particular to a drug target, use and oral drug for inhibiting tumors.

Background technique

Inhibiting cancer cell translation can effectively suppress cancer cell growth and has drug development value. However, inhibiting the translation process may cause serious cytotoxicity. The main reasons are: translation inhibitors occupy ribosome resources, cause cell stress, protein folding disorder, etc. These factors will affect the clinical application prospects of translation inhibition-related drugs.

In some current related technologies, small molecule compounds or mimetics that inhibit single translation initiation factors have been developed to affect their enzyme activity, functional structure, modification abundance, etc., so as to achieve the purpose of inhibiting translation initiation. For example, Elatol, SAN and 15d-PGJ2 that have been developed can inhibit EIF4A1 (PMID: 32014999). However, such inhibitors are prone to cause cellular integrated stress response (ISR) (PMID: 32014999). ISR is an adaptive cellular mechanism that can non-specifically inhibit overall cellular protein synthesis, allowing cells to respond to stress and survive (PMID: 27629041).

The core of this pathway is the phosphorylation of eIF2α, which is used to inhibit global protein synthesis while allowing the expression of selected mRNAs. Although the ISR is primarily a homeostatic program that promotes survival, exposure to severe stress drives signal transduction to cell death, leading to cytotoxicity. For example, it has been reported that in the treatment of breast cancer, paclitaxel treatment can induce ISR to provide a survival advantage for cancer in vivo (PMID: 31211507). The reason is that the ISR can translate IRES-dependent uORF proteins, such as oncogenes SOX2, MYC, HER2, etc., which can be preferentially translated under ISR induction, allowing cancer cells to resist adversity, leading to cancer resistance and recurrence.

Therefore, there is still an urgent need to find suitable drug targets in this field to achieve precise targeted treatment of cancer.

Summary of the invention

In view of this, the present application aims to provide a drug target that can effectively inhibit tumors, especially inhibit malignant phenotypes such as cancer cell proliferation, metastasis and tumor formation, so as to achieve precise targeted treatment of cancer while avoiding side effects.

In the first aspect, a drug target for inhibiting tumors is provided, wherein the drug target is the eukaryotic translation initiation factor EIF2. EIF2 is a protein complex composed of multiple constituent proteins, and its structure is, for example, found in Tomas Adomavicius et al. (“The structural basis of translational control by eIF2 phosphorylation”, Nature Communication, May 13, 2019, Article number: 2136 (2019), https://www.nature.com/articles/s41467-019-10167-3). In some embodiments, the drug target is EIF2S1, a subunit of the initiation factor EIF2. For example, the protein sequence of EIF2S1 can be found in RefSeq ID: NP_004085 of the NCBI library. In some embodiments, the drug is aurintricarboxylic acid (ATCA) or its ammonium salt.

By inhibiting the translation initiation factor EIF2, its phosphorylation can be effectively reduced, thereby inhibiting ISR. At the same time, inhibiting the translation initiation factor EIF2 can prevent the ribosome from assembling to initiate translation, without consuming ribosome resources and making it difficult to produce various stress responses in the cell, thereby achieving the effect of safely inhibiting cancer cells.

In some embodiments, the tumor is a malignant tumor selected from the group consisting of: malignant epithelial tumors, sarcomas, myelomas, leukemias, lymphomas, melanomas, head and neck tumors, brain tumors, peritoneal cancer, mixed tumors, and childhood malignancies.

In some further embodiments, the malignant epithelial tumor is selected from the group consisting of lung cancer, breast cancer, liver cancer, pancreatic cancer, colorectal cancer, gastric cancer, gastroesophageal adenocarcinoma, esophageal cancer, small intestine cancer, cardia cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, vulvar cancer, testicular cancer, prostate cancer, penile cancer, kidney cancer, bladder cancer, anal cancer, gallbladder cancer, bile duct cancer, teratoma and cardiac tumor.

In some embodiments, the tumor is lung cancer, preferably non-small cell lung cancer.

In some embodiments, the tumor is ovarian cancer, preferably ovarian epithelial cancer.

In some embodiments, the tumor is liver cancer.

In a second aspect, a use of the eukaryotic translation initiation factor EIF2 as a drug target for inhibiting tumors is provided.

In some embodiments, the drug is aurintricarboxylic acid (ATCA) or its ammonium salt.

In a third aspect, provided is the use of a substance that inhibits the eukaryotic translation initiation factor EIF2 in the preparation of a drug for treating tumors.

In some embodiments, the substance is aurintricarboxylic acid (ATCA) or its ammonium salt.

In a fourth aspect, an oral drug for inhibiting tumors is provided, which comprises an inhibitor that can target the drug target eukaryotic translation initiation factor EIF2 and inhibit it without causing phosphorylation. In some embodiments, the inhibitor is aurintricarboxylic acid (ATCA) or its ammonium salt.

In summary, the present invention can achieve the following beneficial technical effects.

Inhibiting eukaryotic translation initiation by inhibiting the translation initiation factor EIF2 can safely suppress the malignant phenotype of cancer cells, thereby achieving at least the following safety:

1. Unlike other commonly used translation initiation inhibitors (such as CHX and HTT), targeted inhibition of EIF2 does not occupy ribosome resources and can competitively bind to ribosomes; for example, CHX not only inhibits translation initiation, but also inhibits translation elongation, thus stimulating more stress responses and having greater side effects;

2. It does not cause ISR in cells and can reduce the toxicity to normal cells;

3. It is safe to take orally.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG1 is a thermal shift protein immunoblot image of ATCA binding to EIF2S1.

FIG2 is a schematic diagram of molecular docking for evaluating the binding energy and interaction mode of ATCA with its target protein EIF2S1.

Figure 3 is the result of immunoblotting detection of EIF2A phosphorylation protein, in which the left lane is the control and the right lane is the result after treatment with 1mM ATCA for 48 hours.

FIG. 4 is an electrophoresis diagram showing the down-regulation of SOX2 and HER2 after ATCA treatment.

FIG5 is a graph showing the results of a polysome profiling experiment.

Figure 6 is a Western Blot image for detecting the nascent peptide.

FIG7 shows that ATCA inhibits the signaling pathways associated with the malignant phenotype of cancer, specifically showing the KEGG pathway enrichment results of down-regulated genes after 48 hours of drug treatment.

Detailed ways

The present application will be further described in detail below in conjunction with specific embodiments.

In order to develop drugs that can effectively inhibit cancer cell translation, the inventors of this application have conducted a lot of research. The results unexpectedly found that by inhibiting the translation initiation factor EIF2, its phosphorylation can be effectively reduced, thereby inhibiting ISR. At the same time, inhibiting the translation initiation factor EIF2 can prevent the ribosome from assembling to initiate translation, does not consume ribosome resources, and is not prone to various stress responses in cells, thereby achieving the effect of safely inhibiting cancer cells.

At the same time, the inventors of the present application found in the research process that aurintricarboxylic acid (ATCA) can target and bind to the subunit EIF2S1 of the translation initiation factor EIF2, but does not affect its phosphorylation abundance, which means that it does not cause ISR. The expression of SOX2 and HER2 proteins was downregulated, indicating that the cells did not undergo the ISR-dependent SOX2 and HER2 small open reading frame translation events (uORFs) triggered by EIF2S1. In addition, experiments have also proved that ATCA only targets and binds to the subunit EIF2S1 of the translation initiation factor EIF2, but does not bind to the non-target proteins EEF2 and Vinculin.

The present invention has been accomplished based on the above findings.

The embodiments of the present invention will be described in detail below in conjunction with specific examples. Those skilled in the art will understand that the purpose of providing these examples is only to illustrate some exemplary ways in which the present invention can be implemented, and is not intended to limit the scope of the present invention to these exemplary embodiments.

Example 1: Thermal transfer immunoblotting CESTA-WB experiment

CESTA-WB experiment: H1299 cells were plated in 15 cm dishes and cultured until the density reached about 90%-100%. The culture medium was aspirated and washed twice with PBS. 2 mL Lysis Buffer (RB Buffer, 10% N-Dodecyl-β-D-maltoside, 1× protease inhibitor) was added to each dish and placed flat on ice for lysis for 30 minutes. The cell lysate was collected and centrifuged at 17000g and 4°C for 10 minutes. The supernatant was quantified using a BCA kit. 45uL of total protein was taken into PCR tubes, and ATCA was added to the final concentrations of 10mM, 1mM, 100uM, 10uM, 1uM, 100nM, and 10nM, respectively. The tubes were left standing at 25° for 30 minutes to allow ATCA to fully bind to the protein. Two other tubes were taken without ATCA as controls. The experimental group was treated at 55°C for 3 minutes, one tube of the control group was treated at 37°C for 3 minutes, and the other tube of the control sample was treated at 50°C for 3 minutes; centrifuged at 4°C, 17000g for 10 minutes to remove denatured proteins, and the supernatant was placed in a new PCR tube. 5ug of supernatant was added to 5×SDS Loading Buffer, denatured in a 100°C water bath, and Western Blot was used to detect the quantitative trends of EEF2, EIF2S1, β-actin and Vinculin proteins.

Western Blot: Load samples and prestained protein molecular weight standards onto SDS-PAGE gel (10cm x 10cm) and run at 100V for 40min. Electrophoresis of proteins from SDS-PAGE was performed at 100V, 230mA for 1h. After transfer, wash the nitrocellulose membrane with 25ml TBS for 5min at room temperature. Incubate the membrane in 25mL blocking buffer (TBST, 5% skim milk) at room temperature for 1h. Wash three times with 15ml TBST for 5min each. Incubate the membrane and primary antibodies for EEF2, EIF2S1, β-actin and Vinculin (diluted 1:1500) in 10mL primary antibody dilution buffer at 4°C overnight with gentle shaking. Wash three times with 15mL TBST for 5min each. Prepare rabbit secondary antibody at 1:2000 using 5% skim milk and incubate at room temperature for 1.5h. Wash three times with 15mL TBST for 5min each. The membrane was mixed with 10 mL

(0.5ml 20X

#7003, 0.5 mL 20X peroxide and 9.0 mL purified water) and incubate at room temperature for 1 min with gentle agitation. Drain the excess developer on the membrane (do not let it dry), wrap it in plastic film, and then develop it with a BIO-RAD developer. The results are shown in Figure 1.

As can be seen from Figure 1, ATCA targets the binding protein EIF2S1 (one of the constituent proteins of eIF2), but does not bind to the non-target proteins EEF2 and Vinculin.

Example 2 Molecular docking analysis: Evaluation of the binding energy and interaction pattern between ATCA and its target protein EIF2S1

In order to evaluate the binding energy and interaction mode of ATCA with its target protein EIF2S1, protein-ligand docking analysis was performed using AutoDock Vina 1.2.2 (PMID: 19499576). First, the molecular structure of ATCA was obtained from the PubChem compound database (https://pubchem.ncbi.nlm.nih.gov/), as shown in the following formula (1).

Then, the protein EIF2S1 (PDB number: 6ybv; resolution:

). Protein and ligand files were prepared first. All protein and molecule files were converted to PDBQI format, all water molecules were removed, and polar amino acid atoms were added. The grid box was centered to cover each protein domain and accommodate free molecular motion. The docking pocket was set to a

The square pocket of the molecule was 0.05 nm in grid distance. The molecular docking study was performed by AutoDockVina 1.2.2 (http://autodock.scripps.edu/) for model visualization. The analysis results are shown in Figure 2.

As shown in Figure 2, the results of molecular docking show the most stable docking conformation. ATCA can penetrate deep into the pocket of EIF2S1 and form multiple stable hydrogen bonds with Lys142, Pro144, His10, Lys96 and Val18 subunits, with a binding energy of -6.7 kcal/mol. This shows that it can form an effective non-covalent bond and occupy its pocket site, which will inhibit its function and can dissociate, which is a competitive binding. In this way, the degree of inhibition of EIF2S1 can be easily adjusted by adjusting the concentration of ATCA, or the inhibition of EIF2S1 can be lifted by removing ATCA, so as to achieve flexible control on demand.

Example 3 Immunoblotting detection of EIF2A phosphorylation protein

Western Blot method: Load the sample and prestained protein molecular weight standard onto SDS-PAGE gel (10cm x 10cm) and run at 100V for 40min. Treat at 100V, 230mA for 1 hour, and then transfer the protein in SDS-PAGE to nitrocellulose membrane. After transfer, wash the nitrocellulose membrane with 25ml TBS for 5min at room temperature. Place the membrane in 25mL blocking buffer (TBST, 5% skim milk) and incubate at room temperature for 1 hour. Wash three times with 15ml TBST, 5min each time. Incubate the membrane and phosphorylated EIF2S1 primary antibody (diluted 1:1500) in 10mL primary antibody dilution buffer at 4°C overnight with regular gentle shaking. Wash three times with 15mL TBST, 5min each. Use 5% skim milk to prepare 1:2000 rabbit secondary antibody and incubate at room temperature for 1.5h. Wash three times with 15mL TBST, 5min each time.

(0.5ml20X

0.5 mL 20X peroxide and 9.0 mL ultrapure water) and incubate at room temperature for 1 min with periodic gentle agitation. Drain the excess developer from the membrane (do not dry it), wrap it in plastic film, and then develop it using a BIO-RAD developer.

The results are shown in Figures 3 and 4. As can be seen from Figure 3, ATCA can target and bind to EIF2S1, but does not affect its phosphorylation abundance, which means that it does not cause ISR. As can be seen from Figure 4, SOX2 and HER2 protein expression is downregulated, indicating that the cells do not undergo EIF2S1-induced ISR dependent on SOX2 and HER2 small open reading frame translation events (uORF).

Example 4 Determination of translation initiation efficiency and detection of nascent peptides in cells

Polysome profiling: Cells were plated in 75T flasks, 2 million cells per flask. After 24 hours of attachment, ACTA was added to the experimental group to make the working solution concentration 1 mg/ml. The control group replaced with new culture medium. After 24 and 48 hours of ATCA treatment, samples were collected, the culture medium was aspirated, and the cells were washed twice with PBS. 2 ml Lysis Buffer (RB Buffer, 1% Ttiton X-100, 10 μg/μL cycloheximide) was added to each flask and lysed on ice for 30 minutes. The lysate was aspirated into an RNase-free EP tube. Centrifuged at 4°C and 17,000 g for 10 minutes, 1.5 ml of supernatant was aspirated into a new EP tube and added to the pre-prepared sucrose density gradient solution (sucrose concentration from top to bottom: 13%-46%, each gradient increases by 3% concentration). Centrifuge at 4°C and 25400rpm for 4 hours and 10 minutes, and use high performance liquid chromatography to perform relative quantitative analysis of polysomes, monosomes, and ribosome subunits. The results are shown in Figure 5. As shown in Figure 5, 24 hours after drug addition, the polysome distribution curve did not change much; 48 hours after drug addition, the polysome fraction was significantly reduced, and it mainly existed in the form of monosomes. Since ATCA does not affect translation elongation, it means that translation initiation has been effectively slowed down, resulting in only one ribosome translating on most mRNAs.

Detection of nascent peptides: cells were plated in 6-well plates, 200,000 cells in each well. ATCA was added after 24 hours of attachment to the plate, with the working solution concentration being 1 mg/ml. New culture medium was used for the control group, and the cells were treated for 2, 6, 12, 24, and 48 hours, respectively. No ATCA was added to the control group. Actinomycin was added to the positive control group 25 minutes before sampling for 10 minutes, and then 10ug/ul of puromycin was added to all wells to label the nascent peptides for 15 minutes. The culture medium was aspirated, the cells were washed twice with PBS, and IP&WB lysis buffer was added for lysis on ice for 30 minutes. The cells were centrifuged at 12,000 g at 4°C for 20 minutes, and the supernatant was aspirated into a new centrifuge tube. 10ug of protein was added to 5×SDS Loading Buffer, and the cells were denatured in a water bath at 100°C for 10 minutes. Quantitative detection was performed by Western Blot.

Western Blot method: Load the sample and prestained protein molecular weight standard onto SDS-PAGE gel (10cm x 10cm) and electrophoresed at 100V for 40min. Transfer the protein in SDS-PAGE to nitrocellulose membrane at 100V, 230mA, 1h. After transfer, wash the nitrocellulose membrane with 25ml TBS for 5min at room temperature. Place the membrane in 25mL blocking buffer (TBST, 5% skim milk) and incubate at room temperature for 1 hour. Wash three times with 15ml TBST, 5min each time. Place the membrane and puromycin primary antibody (diluted 1:1000) in 10mL primary antibody dilution buffer and incubate overnight at 4°C with gentle shaking from time to time. Wash three times with 15mL TBST, 5min each time. Use 5% skim milk to prepare 1:2000 rabbit secondary antibody and incubate at room temperature for 1.5h. Wash three times with 15mL TBST, 5min each time. Mix the membrane with 10mL

(0.5mL 20X

0.5 mL 20X peroxide and 9.0 mL ultrapure water) and incubate at room temperature for 1 min with gentle agitation. Drain the excess developer from the membrane (do not let it dry), wrap it in plastic film, and then develop it using the BIO-RAD developer. The results are shown in Figure 6.

As shown in Figure 6, puromycin will covalently bind itself as an "amino acid" to the end of the nascent peptide chain and fall off the ribosome. The nascent peptide chains with puromycin at the end can be seen using puromycin antibodies. Figure 6 shows that after 2-12 hours of drug addition, protein synthesis has not been significantly blocked; after 24-48 hours of drug addition, the nascent peptide chains are significantly reduced compared to when no drug is added, proving that ATCA's ability to inhibit translation initiation can effectively reduce protein synthesis.

Example 5 Transcriptome Sequencing

Transcriptome sequencing experimental steps:

RNA extraction

Add 1 mg/mL ATCA to the culture medium of a T75 cell culture flask filled with three million H1299 cells as the treatment group, and add an equal volume of PBS as the control group. After 48 hours of ATCA treatment, discard the culture supernatant, put it on ice, and wash it twice with pre-cooled PBS. Discard all PBS, add 5 mL of pre-cooled Trizol (total RNA extraction reagent), and shake thoroughly to mix. The specific extraction operation is as follows:

1) Add 0.2 mL of chloroform per 1000 μL of Trizol, mix vigorously (vortex) for 15 seconds, and leave at room temperature for 3 minutes. The sample can be observed to begin to separate into layers;

2) Centrifuge at 12000×g, 4°C for 15 min to separate the sample into three layers;

3) Carefully aspirate the upper aqueous phase, about 600 μL, and transfer it to a new 1.5 mL EP tube. Be careful not to aspirate the middle layer of liquid during the operation;

4) Add 800 μL of isopropanol and invert to mix;

5) Place at -20℃ for 8h;

6) After 8 h, centrifuge at 12,000 × g, 4 °C for 30 min and remove the supernatant;

7) Add 1 mL 75% ethanol (needs to be pre-cooled at -20°C for 30 min);

8) Centrifuge at 7500 × g, 4°C for 5 min and remove the supernatant;

9) Repeat steps 7) and 8) once;

10) Remove the residual ethanol, open the tube cap, and air-dry for 5 minutes;

11) Add about 30 to 60 μl of RNase Free pure water to dissolve the particles according to their size. This step will yield the RNA standard, which should be stored in a -80° refrigerator.

Poly-A mRNA Enrichment:

The library construction and sequencing process were carried out according to the standard transcription of human poly-A mRNA. For specific experimental steps, please refer to the applicant's published literature (PMID: 23519614, PMID: 30265008).

This process uses the Novozymes poly-A mRNA enrichment kit to enrich poly-A mRNA. See the instructions for specific steps:

Total poly-A mRNA was extracted using the VAHTS mRNA Caputre Beads kit, which included the following steps:

1) Take out the mRNA Caputre Beads and let them stand to equilibrate to room temperature;

2) Prepare RNA samples: In a Nuclease-free PCR tube, dilute 0.01-12.5 μg of total RNA to 50 μL with RNase-free water and place on ice until ready to use;

3) Turn the mRNA Caputre Beads upside down and mix thoroughly; pipette 50 μL into the total RNA sample and mix well;

4) Place the sample in a PCR instrument, incubate at 65°C for 5 min, 25°C for 5 min, and maintain at 4°C to allow the mRNA to bind to the magnetic beads;

5) Place the sample on a magnetic rack for 5 minutes to separate mRNA from total RNA, and remove the supernatant;

6) Take the sample out of the magnetic rack, add 200 μL Beads wash buffer, mix well with a pipette, let it stand on the magnetic rack for 5 minutes, and remove the supernatant;

7) Remove the sample from the magnetic rack, add 50 μL Tris Buffer to resuspend the magnetic beads, and mix well with a pipette;

8) Place the sample in a PCR instrument, incubate at 80°C for 2 min, maintain at 25°C, and elute the mRNA;

9) Add 50 μL Bead Binding Buffer and mix well with a pipette;

10) Leave at room temperature for 5 minutes to allow the mRNA to bind to the magnetic beads;

11) Place the sample on a magnetic rack for 5 minutes to separate mRNA from total RNA; remove the supernatant;

12) Remove the sample from the magnetic stand, add 200 μL Beads Wash Buffer, mix well, place on the magnetic stand for 5 minutes, remove the supernatant, and obtain total mRNA.

Transcriptome library:

The library was constructed using the MGI transcriptome library construction kit. PE150 sequencing was performed using the MGIseq2000 high-throughput sequencing platform. The sequencing main data used the FANSe3 alignment algorithm to align reads to the human transcriptome reference sequence with the parameters -L80 -E5 -I0 -S14 -B1 -U0.

Differential gene screening and enrichment analysis:

The edgeR was used to screen the differentially expressed genes (up or down-regulated by more than 2 times, P less than 0.05) between the two sets of transcriptome sequencing data. The KEGG database was used to perform gene function and pathway enrichment analysis on the down-regulated genes, and representative pathways with P values less than 0.01 were displayed.

The results are shown in Figure 7. As shown in Figure 7, the most significantly downregulated pathway is cell cycle, which is one of the most important pathways for cancer cells to maintain rapid proliferation and growth. In addition, the significantly downregulated pathways also include platinum drug resistance, TGF-beta signaling pathway, signaling pathways regulating pluripotency of stem cells, FoxO signaling pathway, and other pathways that contribute significantly to the occurrence and development of cancer. This shows that ATCA can inhibit these cancer-promoting pathways more comprehensively and effectively suppress the malignant phenotype of cancer cells.

In addition, the LDH method was used to determine the cytotoxicity of ATCA and detect the cytotoxicity of the drug. The results showed that at a concentration of 0.5 mg/ml ATCA, no obvious cytotoxicity was caused to cancer cells and normal cells, and the various physiological activities of normal cell HBE were normal, indicating that it had no obvious killing effect on normal cells, that is, no cytotoxicity.

In the experiment of ATCA-induced apoptosis of lung cancer cells, Annexin V and propidium iodide were used to stain the cancer cells, and then flow cytometry was used to detect that under the action of 0.5 mg/mL ATCA, lung adenocarcinoma cells A549 and H1299 showed obvious apoptosis (P < 0.05, n = 4), while normal lung cells HBE did not show apoptosis, indicating that ATCA can induce apoptosis of cancer cells without killing normal cells.

In addition, in other experiments, ATCT can induce apoptosis of ovarian cancer cells and inhibit the proliferation of liver cancer cells.

The above are all preferred embodiments of the present application, and the protection scope of the present application is not limited thereto. Therefore, any equivalent changes made according to the structure, shape, and principle of the present application should be included in the protection scope of the present application.

Claims

A drug target for inhibiting tumors, characterized in that the drug target is the eukaryotic translation initiation factor EIF2.
The drug target according to claim 1 is characterized in that the drug target is the subunit EIF2S1 of the initiation factor EIF2.
The drug target according to claim 1, characterized in that the drug is an EIF2 inhibitor selected from aurintricarboxylic acid (ATCA) or its ammonium salt.
The drug target according to claim 1, characterized in that the tumor is a malignant tumor selected from the group consisting of: malignant epithelial tumors, sarcomas, myeloma, leukemia, lymphoma, melanoma, head and neck tumors, brain tumors, peritoneal cancer, mixed tumors and childhood malignant tumors.
The drug target according to claim 4, characterized in that the malignant epithelial tumor is selected from the group consisting of lung cancer, breast cancer, liver cancer, pancreatic cancer, colorectal cancer, gastric cancer, gastroesophageal adenocarcinoma, esophageal cancer, small intestinal cancer, cardia cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, vulvar cancer, testicular cancer, prostate cancer, penile cancer, kidney cancer, bladder cancer, anal cancer, gallbladder cancer, bile duct cancer, teratoma and cardiac tumor.
The drug target according to claim 4, characterized in that the tumor is lung cancer, preferably non-small cell lung cancer.
The drug target according to claim 4, characterized in that the tumor is ovarian cancer, preferably ovarian epithelial cancer.
The drug target according to claim 4, characterized in that the tumor is liver cancer.
Use of a substance that inhibits eukaryotic translation initiation factor EIF2 in the preparation of a drug for treating tumors.
The use according to claim 9, wherein the substance is aurintricarboxylic acid (ATCA) or its ammonium salt.
An oral drug for inhibiting tumors comprises an inhibitor that can target the drug target, the eukaryotic translation initiation factor EIF2, and inhibit it without causing phosphorylation.
The oral drug according to claim 11, characterized in that the inhibitor is aurintricarboxylic acid (ATCA) or its ammonium salt.