Application of compound in preparation of PHGDH active site inhibitor

Abstract

The invention provides application of a compound in preparation of a PHGDH active site inhibitor, and belongs to the technical field of PHGDH inhibitors. According to the present invention, the PHGDH active site inhibitor is predicted based on the computer-aided drug design for the first time, the new PHGDH active site targeting inhibitor is provided, and the PHGDH active site targeting inhibitor comprises at least one of P-3101, P-3102, P-3103, P-3104, P-3105, P-3106, P-3107 and P-3108. Molecular docking research shows that the active site inhibitor provided by the invention realizes inhibition activity by occupying key residues combined with NAD < + > in PHGDH. The structure-activity relation of the active site inhibitor is defined through docking analysis, and important guidance is provided for designing more efficient PHGDH targeting anti-cancer drugs.

Description

Technical Field

[0001] The invention belongs to the technical field of PHGDH inhibitors, and particularly relates to application of a compound in preparing a PHGDH active site inhibitor. Background Art

[0002] Serine is a molecule classified as a non-essential amino acid that plays a variety of important roles in cellular metabolism. In general, serine promotes cell growth and proliferation by providing key intermediates for the synthesis of nucleotides, lipids, amino acids, and cofactors. In cells, the mechanisms for maintaining the stability of the serine pool include four pathways: the first is de novo synthesis through the serine synthesis pathway (SSP); the second is through glycine conversion; the third is through dietary intake; and the fourth is through phospholipid degradation. Among these pathways, studies have shown that de novo synthesis is the main source of serine in mammalian cells.

[0003] As cancer research deepens, people have summarized the increase in SSP flux into two aspects: on the one hand, enzymes in SSP (such as D-3-phosphoglycerate dehydrogenase, PHGDH) are overexpressed in at least 11 types of cancer cells; on the other hand, a variety of factors in cancer cells can directly or indirectly activate SSP, such as activating transcription factor 4 (ATF4), histone lysine demethylase (KDM4C) and H3K9 methyltransferase (G9A). Research observations have shown that stable knockdown of PHGDH expression can significantly inhibit the growth of PHGDH-overexpressing tumors in vivo and in vitro, but has almost no significant effect on the growth of tumors with normal PHGDH expression. Therefore, enzymes in SSP are considered to be promising targets for cancer therapy. At present, the development of inhibitors for SSP enzymes is still in its early stages, and the discovery of effective inhibitors in this pathway will help deepen the understanding of the biological functions of these metabolic enzymes.

[0004] PHGDH is a tetrameric enzyme that catalyzes the initiation reaction of SSP, using 3-phosphoglycerate (3PG), an intermediate of glycolysis, as a substrate and converting NAD + Reduced to NADH. In recent years, important progress has been made in the study of the function of PHGDH in tumorigenesis. For example, PHGDH can catalyze α-ketoglutarate (αKG) to produce the carcinogenic metabolite D-2-hydroxyglutarate (D-2HG); PHGDH can stabilize the cell cycle-related protein FOXM1, thereby promoting the growth and proliferation of cancer cells; in the absence of glucose, PHGDH can help PKCξ-deficient cancer cells obtain their essential energy glutamine. In addition, stable knockdown of PHGDH combined with metabolic stress can accelerate cancer cell apoptosis. Therefore, designing inhibitors against PHGDH has medical therapeutic prospects.

[0005] Since 2016, a variety of PHGDH inhibitors have been reported. These inhibitors can be divided into two categories according to their mode of action: one is NAD + Noncompetitive inhibitors, such as CBR-5884 (IC 50 =33 μM), NCT-503 (IC 50 =2.5 μM), P-2101 (IC 50 =34.8 μM) and P-2201 (IC 50 =35.7 μM), α-thioamide inhibitors and their analogs (IC 50 =10.4 μM), Azacoccone E (IC 50 =9.8μM), Ixocarpalactone A (lox A, IC 50 =1.4 μM) and disulfiram (DSF, IC 50 =0.59μM). The second type is NAD + Competitive inhibitors, such as Newcastle PHGDH inhibitor (ITC, KD = 2-17 mM), AstraZeneca PHGDH inhibitor (SPR, KD = 0.18 μM) and their derivatives (IC 50 =1.46 μM), and BI-4924 (IC 50 =3nM). Among the reported PHGDH inhibitors, BI-4924 exhibited the best PHGDH enzyme inhibitory activity. BI-4924 occupied the cofactor binding site of PHGDH, rather than the substrate binding site. However, due to the poor membrane permeability of BI-4924, its half maximal effective inhibitory concentration (EC 50 ) is only 2.2 μM. Therefore, there is an urgent need in the art to design new inhibitors with therapeutic prospects for PHGDH. Summary of the invention

[0006] In view of this, the object of the present invention is to provide a compound for use in preparing a PHGDH active site inhibitor.

[0007] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0008] The present invention provides an application of a compound in the preparation of a PHGDH active site inhibitor, wherein the compound comprises at least one of P-3101, P-3102, P-3103, P-3104, P-3105, P-3106, P-3107 and P-3108; the P-3101 is The P-3102 is The P-3103 is The P-3104 is The P-3105 is The P-3106 is The P-3107 is The P-3108 is

[0009] The present invention predicts PHGDH active site inhibitors based on computer-aided drug design (CADD) for the first time. + In the PHGDH enzyme activity assay, eight inhibitors, P-3101, P-3102, P-3103, P-3104, P-3105, P-3106, P-3107 and P-3108, showed differences in PHGDH inhibitory activity. P-3105, as an analog of BI-4924, showed the best PHGDH inhibitory ability (IC 50 , low value: 1.9±0.4μM, IC 50 , high value: 9.3±0.4μM) and binding capacity (K D :40±18nM). Through NanoDSF detection, the present invention proves that the above eight active site inhibitors can stabilize the structure of PHGDH in a dose-dependent manner. Molecular docking studies clarify the binding modes of the above eight active site inhibitors and analyze the effects of their structures on the corresponding binding modes.

[0010] For drug discovery research, it is crucial to verify whether the identified drug is a pan-target interference compound (PAINS). If the compound is a PAINS, a series of verification experiments are required to exclude its universal interference. It has been verified that all PHGDH active site inhibitors of the present invention, except P-3106, are not PAINS. In theory, the binding affinity (K D value) should be related to its enzyme inhibition ability (IC 50 In the experiments of the present invention, the K of the active site inhibitor D The values ​​are usually 1-2 orders of magnitude lower than the inhibitory activity. For example, the K D The value was 40 nM, and its PHGDH inhibitory activity IC 50 The value is about 1.9 μM. D and IC 50 The difference between the values ​​is mainly due to the addition of NAD + These results also support the conclusion of the present invention that the inhibitor binds to the active site. +The binding site inhibits PHGDH activity, on the other hand, possibly by restricting the movement of the rigid domains and preventing the closure of the active site, thereby stabilizing PHGDH in an inactive conformation.

[0011] The present invention also provides the use of a PHGDH active site inhibitor in the preparation of a tumor treatment product, wherein the PHGDH active site inhibitor comprises at least one of P-3103, P-3104, P-3107 and P-3108, wherein P-3103 is The P-3104 is The P-3107 is The P-3108 is

[0012] In the application of the present invention, the tumor preferably includes breast cancer, the breast cancer preferably includes mammary ductal carcinoma, and the product preferably includes a drug.

[0013] The present invention also provides a drug for treating tumors, wherein the active ingredients of the drug include at least one of P-3103, P-3104, P-3107 and P-3108, wherein P-3103 is The P-3104 is The P-3107 is The P-3108 is

[0014] In the present invention, at least one of P-3103, P-3104, P-3107 and P-3108 is preferably the sole active ingredient of the drug. In the drug of the present invention, the tumor preferably includes breast cancer, and the breast cancer preferably includes mammary ductal carcinoma. In the present invention, the dosage form of the drug preferably includes oral solution, injection, tablet, pill, dispersant, capsule or granule. The present invention has no special limitation on the excipients in the drug, and conventional pharmaceutical excipients in the art can be used.

[0015] Beneficial effects of the present invention:

[0016] The present invention predicts PHGDH active site inhibitors based on computer-aided drug design for the first time, provides new inhibitors targeting the PHGDH active site, and studies the structure-activity relationship between the PHGDH active site inhibitor and PHGDH. Molecular docking studies show that the active site inhibitor provided by the present invention occupies NAD +The key residues bound achieved inhibitory activity. Further analysis showed that active site inhibitors containing flexible chains and hydrogen bond donors in the middle of the structure may have a binding mode similar to that of the reported PHGDH inhibitor BI-4924. The docking analysis of the present invention clarifies the structure-activity relationship of active site inhibitors and provides important guidance for the design of more efficient anticancer drugs targeting PHGDH. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 This is the docking site result calculated by the Cavity program. Only one site is shown in the figure for clarity;

[0018] Figure 2 For low NAD + Enzyme dose-response curves for PHGDH at different ratios, where A to H are the results of P-3101 to P-3108, respectively;

[0019] Figure 3 For high NAD + Enzyme dose-response curves for PHGDH at different ratios, where A to H are the results of P-3101 to P-3108, respectively;

[0020] Figure 4 are the SPR sensorgrams of P-3101 to P-3108 and their corresponding fitting curves, wherein A to H are the SPR sensorgrams of P-3101 to P-3108 and their corresponding fitting curves, respectively;

[0021] Figure 5 The effect of different concentrations of inhibitors on the thermal stability of PHGDH;

[0022] Figure 6 The molecular docking results of PHGDH active site inhibitors, where A is NAD + A is the co-crystal structure of P-3106 (orange) and MLT (cyan) with PHGDH; B is the predicted binding mode of P-3106 (magenta) and P-3107 (orange) in PHGDH; C is the key interaction between BI-4924 (orange) and PHGDH; D is the predicted binding mode of P-3101 (light orange), P-3102 (grey), P-3105 (lime green) and P-3108 (orange) in PHGDH;

[0023] Figure 7 The figures are the inhibitory effects of different compounds on the proliferation of PHGDH-sensitive breast cancer cells MDA-MB-468 and HCC70, where A is the MTT result of MDA-MB-468 cells; B is the MTT result of HCC70 cells. DETAILED DESCRIPTION

[0024] The technical solutions provided by the present invention are described in detail below in conjunction with the embodiments, but they should not be construed as limiting the protection scope of the present invention.

[0025] In the following embodiments, unless otherwise specified, all of them are conventional methods.

[0026] Unless otherwise specified, the materials and reagents used in the following examples can be obtained from commercial sources.

[0027] Example 1

[0028] Virtual screening

[0029] The crystal structure of human PHGDH (PDB ID: 2G76) was obtained from the Protein Data Bank (PDB, http: / / www.rcsb.org). The SPECS library was screened for molecular docking using the standard precise (SP) mode and the extra precise (XP) mode of the Schrodinger Glide module.

[0030] Due to the small molecular weight of 3PG, it may be difficult to obtain inhibitors with good PHGDH inhibitory activity and targeting specificity if only virtual screening is performed on the substrate binding site. Therefore, the PHGDH docking site containing the substrate and cofactor binding sites was generated and calculated using the pocket detection program Cavity. The volume of the docking site is Predicted maximum pK D is 11.01. The docking site is trumpet-shaped (see Figure 1 ), including two binding sites: cofactor binding site and substrate binding site, cofactor NAD + (orange), substrate analog D-malate (MLT, cyan) and key residues in the docking site (green) are represented as sticks, PHGDH is shown in cartoon mode, PHGDH (PDB: 2G76) forms a dimer in the crystal structure, the docking site is present in each monomer, and the cofactor NAD + and the substrate analog MLT binds to two adjacent sites through a narrow channel.

[0031] Finally, two steps of virtual screening and manual selection were performed from the top 1000 compounds screened by XP mode, and 226 compounds were finally screened and purchased from SPECS for testing in the following examples.

[0032] Example 2

[0033] (1) Molecular cloning, protein expression and purification

[0034] The construction of PHGDH and PSAT1 (phosphoserine aminotransferase 1) plasmids, protein expression and purification methods were referred to previous literature. The coding regions of PHGDH and PSAT1 (provided by Seajet Scientific, Beijing, China) were first cloned into the pET21a(+) vector and then transformed into the BL21(DE3) Escherichia coli (E. coli) strain. The lysed recombinant cell supernatant was purified by nickel affinity column (HisTrap HP, Cytiva) and gel filtration column (Sephacryl S-200HR, Cytiva).

[0035] (2) Enzyme experiments

[0036] Enzyme experiments use PHGDH to catalyze the reaction. + The activity of recombinant PHGDH was measured by the change in fluorescence emission at 456 nm (excitation wavelength 338 nm) after oxidation to NADH. The experiment was performed in PHGDH buffer (50 mM HEPES, pH 7.5, 1 mM EDTA). In order to consume the 3-phosphohydroxypyruvate generated by the PHGDH catalytic reaction in time, 3 ng / μl PSAT1 and 3 mM glutamate were added in the experiment. NAD + The concentrations of 3PG and PHGDH were tested in two ratios (final concentrations):

[0037] One is low NAD + : 50 μM NAD + , 200μM 3PG, 1ng / μl PHGDH; second, high NAD + : 500 μM NAD + , 1mM3PG, 1ng / μl PHGDH.

[0038] The final concentration of DMSO in the experimental system was set to 5%. The fluorescence signal was recorded by a BioTek Synergy instrument.

[0039] In the PHGDH enzyme activity assay, the inhibitory activities of the selected 226 compounds were determined. A total of 14 compounds showed more than 30% PHGDH inhibitory activity at 50 μM and were further diluted to determine the half inhibitory concentration (IC 50 ), three biological replicates were performed, and the results were expressed as mean ± standard deviation (SD). The results are shown in Table 1. Figure 2 and Figure 3In order to obtain more efficient PHGDH inhibitors, the SPECS virtual database was used to calculate the three-dimensional analogs of these eight compounds and NAD+ and 3PG, and the results are shown in Table 2. It was confirmed that the eight compounds (P-3101 to P-3108) inhibited PHGDH activity in a dose-dependent manner, and the IC 50 The values ​​are in the micromolar range, among which P-3101, P-3102, P-3105, P-3106, P-3107 and P-3108 have an IC value of 50 μM NAD+. 50 The values ​​were 7.2, 4.4, 4.9, 3.3, 3.1, and 6.1 times lower than those at 500 μM NAD+, respectively. The IC50 value of compound P-3108 was 3.8 μM, which was equivalent to 1.9 μM of P-3105, and P-3105 had the best inhibitory ability. The results of enzymatic experiments confirmed that the six compounds P-3101, P-3102, P-3105, P-3106, P-3107, and P-3108 were NAD+ competitive inhibitors.

[0040] Table 1 Summary of PHGDH active site inhibitors

[0041]

[0042]

[0043] Note: Table 1 a In this experiment, NAD + and 3PG concentrations were 50 μM and 200 μM, respectively; b In this experiment, NAD + The concentrations of ATP and 3PG were 500 μM and 1 mM, respectively.

[0044] Table 2 SPECS IDs of PHGDH inhibitors and their corresponding docking results

[0045]

[0046]

[0047] Note: Table 2 a Indicates that the score is calculated by the Glide program

[0048] To exclude false positives, surface plasmon resonance (SPR) was used to detect the binding affinity of active compounds to PHGDH.

[0049] The SPR experiment was based on previous literature. The SPR analysis was performed using a multi-cycle kinetic / affinity method, and the relevant data were fitted by a steady-state affinity mode or a kinetic 1:1 binding mode. The binding affinity of the compounds to PHGDH was determined by an SPR-based Biacore T200 instrument (Cytiva). PHGDH was immobilized on the surface of a CM5 sensor chip by a standard amino coupling method, using 1xPBS-P running buffer (10mM phosphate buffer, 2.7mMNaCl, 137mM KCl, 0.05% surfactant P-20, pH 7.4) at 25°C. The immobilization level of PHGDH was approximately 3000RU. Compounds with different concentrations containing 5% DMSO were injected into the channel in sequence to evaluate the binding affinity. The reference channel was only activated and blocked to eliminate nonspecific binding of the compound to the chip surface. Residual samples in the pipeline were removed by washing with an additional 30% DMSO. The data were fitted to a 1:1 Langmuir binding model using Biacore T200 analysis software to obtain the binding constant (ka), dissociation constant (kd) and equilibrium dissociation constant (K D ). The present invention takes advantage of the high selectivity, high sensitivity, and high throughput of SPR technology, immobilizes PHGDH on the surface of the CM5 sensor chip, injects different concentrations of inhibitors one by one, and records the response units (RU) in real time, showing the curve as a function of time. As shown in Table 1 and Figure 4 The results showed that P-3101 to P-3108 all effectively bound to PHGDH in a concentration-dependent manner, with the best K D In addition, SPR experiments showed that these inhibitors did not aggregate under the experimental conditions.

[0050] Example 3

[0051] The inhibitor of the present invention binds to PHGDH and effectively improves the structural stability of PHGDH

[0052] The effects of compounds P-3101, P-3102, P-3105, P-3106, P-3107 and P-3108 on the melting temperature of PHGDH were determined using the Prometheus NT.48 instrument from NanoTemper Technologies. Capillaries containing 0.1 mg / ml PHGDH and different concentrations of active compounds were placed in a sample tray, and 5% DMSO-treated PHGDH was used as a control. The temperature gradient was increased from 25°C to 95°C at a rate of 1°C / min, while the endogenous fluorescence signals of PHGDH at 330nm and 350nm were recorded. The data are representative values ​​of three biological replicates and are expressed as mean ± standard deviation (SD).

[0053] The fluorescence emission changes of endogenous tryptophan during the thermal unfolding of PHGDH were monitored by Prometheus NT.48, and its denaturation midpoint temperature (T m ). PHGDH T in 5% DMSO m The value was 48.5±0.1℃. After adding different concentrations of compounds, the T m The value increases with the concentration, see Figure 5 P-3105 at 200 μM increased T m The value increased by 5 °C. The thermal stability experiment showed that these inhibitors indeed bound to the active site of PHGDH and improved its structural stability in a dose-dependent manner.

[0054] Example 4

[0055] Molecular docking study of PHGDH active site inhibitors

[0056] The molecular docking software Glide accurately predicted the protein-small molecule interaction geometry between PHGDH and the inhibitor. + and MLT), and the binding modes of P-3101, P-3102, P-3105 and P-3108 (reference BI-4924) are as follows Figure 6 As shown. Glide docking was performed using the crystal structures of PHGDH (PDB codes: 2G76 (B) and 6RJ6 (D)). PHGDH is shown in cartoon mode. NAD + , MLT, BI-4924, inhibitors, and key residues (green) are represented by sticks. Hydrogen bonds are represented by dashed lines. Water-mediated hydrogen bonds are not labeled.

[0057] NAD was obtained from the PDB database + and the co-crystal structure of MLT and PHGDH (PDB code: 2G76) (see Figure 6 A). MLT is a structural analogue of 3PG and is used to replace 3PG to avoid chemical reactions. NAD + It binds to MLT at the docking site mainly through hydrogen bonds and electrostatic interactions. The carboxyl terminus of MLT forms five direct hydrogen bonds with Arg53, Thr77, Arg134, Arg235 and His282 respectively. NAD + Located on the upper side of the docking site, its nicotinamide group interacts with the main chain of Cys233 and the side chain of Asp259. +The ribose and phosphate groups in the PHGDH bind to the main chains of Arg154, Ile155 and Thr206 and the side chain of Asp174 through direct hydrogen bonds. Studies have shown that Asp174 is a key residue in the active site for the interaction between PHGDH and small molecules. Figure 6 A in FIG. 1 shows no water-mediated hydrogen bonding.

[0058] Representative PHGDH inhibitors P-3106 and P-3107 occupy NAD + The docking scores of the binding sites were -6.2 and -7.4 kcal / mol ( Figure 6 B) with NAD + Compared with the binding mode, the benzene ring of P-3106 is located in the adenine binding region, and its nitro and carbonyl groups are bound to the main chains of Ile155 and Ser211 respectively through hydrogen bonds. + In the same binding region of the pyridine ring, the ethoxy oxygen on the benzene ring and the carbonyl oxygen of the oxazole ring are bound to the main chains of Ile155, Arg135 and Arg235 respectively through monocoordinate hydrogen bonds. Since the intermediate structures of P-3106 and P-3107 lack hydrogen bond donors and cannot form hydrogen bonds with the carboxyl oxygen of Asp174, these two inhibitors fail to interact with the key residue Asp174, thus showing weak binding activity.

[0059] In addition, the co-crystal structure of BI-4924 and PHGDH was obtained from the PDB database (PDB code: 6RJ6) ( Figure 6 C). BI-4924 localizes to NAD via two key interactions + The binding site includes strong hydrophobic interactions in the adenine binding region and bidentate hydrogen bonding interactions with Asp174. In addition, BI-4924 also directly interacts with the backbone of Arg154 and Ile155. P-3101, P-3102, P-3105, and P-3108, which are structurally similar to BI-4924, exhibit almost identical binding modes ( Figure 6 D in ). Taking P-3105 as an example, its benzofuranyl group is located in the adenine binding region, and its amide and carboxyl groups interact with Asp174, Arg154 and Ile155 through hydrogen bonds. Combined with the structural optimization process of BI-4924, the halogen substitution of the benzofuranyl group, the methoxy substitution of the hydrazine group and the oxidation of the double bond of the hydrazine group in P-3105 may significantly enhance its inhibitory activity.

[0060] Based on the binding modes of various inhibitors, the study showed that the flexible chain active site inhibitors containing hydrogen bond donors in the middle of the structure tend to extend on the upper side of the docking site, forming a key hydrogen bond with Asp174 and occupying NAD +Binding site. However, active site inhibitors that only contain a rigid ring structure and lack a hydrogen bond donor in the middle can still anchor to NAD + binding site, but it is difficult to form hydrogen bonds with Asp174, thus showing a weaker binding affinity.

[0061] Example 5

[0062] MTT assay was performed for P-3103, P-3104, P-3107, and P-3108 to evaluate the effect of inhibitors on cell viability

[0063] The cell culture method was based on previous studies. MDA-MB-468 (from the China Basic Cell Bank) and HCC70 (from ATCC) were cultured in RPMI-1640 medium (Gibco). RPMI-1640 medium was supplemented with 10% fetal bovine serum, 1% penicillin (100 units / ml) and streptomycin (100 μg / ml). All cells were cultured in an incubator at 37°C and 5% CO2.

[0064] The MTT experimental method was based on previous literature. First, MDA-MB-468 (5000 cells / well) and HCC70 (5000 cells / well) were inoculated in 96-well culture plates and allowed to adhere overnight; then, the cells were treated with three replicates containing different concentrations of compounds or without compounds; then, after 72 hours, 20 μL of 5 mg / ml MTT solution (Thermo Fisher Scientific) was added to each well and incubated for at least 4 hours; then, the medium containing compounds and MTT was removed, and 200 μL of DMSO was added to each well and shaken at 37°C for 10 minutes; finally, the absorbance was measured at 490 nm by a microplate reader (BioTek, Synergy4). The following data are representative values ​​of three biological replicates and are expressed as mean ± standard deviation (SD).

[0065] The antiproliferative activity of the compounds was evaluated using PHGDH-amplified breast cancer cell lines MDA-MB-468 and HCC70. Figure 7 As shown in Figure 3, P-3103, P-3104, P-3107 and P-3108 could significantly inhibit the proliferation of MDA-MB-468 and HCC70 cells, and P-3103, P-3104, P-3107 and P-3108 showed a dose-dependent inhibitory effect on cell activity. 50 The EC values ​​for HCC70 were 16.5±1.2, 0.7±0.1, 2.3±1.0 and 0.5±0.3 μM, respectively. 50 They were 2.7±0.5, 1.2±0.1, 15.6±2.3 and 1.7±0.4 μM respectively.

[0066] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. Use of a compound in the preparation of a PHGDH active site inhibitor, characterized in that: The compound includes at least one of P-3101, P-3102, P-3103, P-3104, P-3105, P-3106, P-3107 and P-3108; the P-3101 is The P-3102 is The P-3103 is The P-3104 is The P-3105 is The P-3106 is The P-3107 is The P-3108 is 2. The use of PHGDH active site inhibitor in the preparation of tumor treatment products, characterized in that: The PHGDH active site inhibitor includes at least one of P-3103, P-3104, P-3107 and P-3108, wherein P-3103 is The P-3104 is The P-3107 is The P-3108 is 3. The use according to claim 2, characterized in that: The tumor includes breast cancer.

4. The use according to claim 3, characterized in that: The breast cancer includes mammary ductal carcinoma.

5. The use according to claim 2, characterized in that: The products include pharmaceuticals.

6. A drug for treating tumors, characterized in that: The active ingredients of the drug include at least one of P-3103, P-3104, P-3107 and P-3108, wherein P-3103 is The P-3104 is The P-3107 is The P-3108 is 7. The drug according to claim 6, characterized in that The tumor includes breast cancer.

8. The drug according to claim 7, characterized in that The breast cancer includes mammary ductal carcinoma.

9. The drug according to claim 6, characterized in that The dosage form of the drug includes oral solution, injection, tablet, pill, dispersant, capsule or granule.

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