CN118580317B - Small molecule peptides targeting degradation of p53 mutants based on p53C176 palmitic acid modification site and their applications - Google Patents
Small molecule peptides targeting degradation of p53 mutants based on p53C176 palmitic acid modification site and their applications Download PDFInfo
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Abstract
The invention provides a small molecule polypeptide XY-0728 of a p53 mutant based on p53C176 palmitic acid modification site and application thereof, wherein the sequence of the small molecule polypeptide XY-0728 is R8-TEVVRRCPHHERC, which shows an effective killing effect on p53 mutant tumors, can kill tumor cells under the same effect, has no toxic or side effect basically on normal cells, has the advantages of high selectivity, weak toxic or side effect and the like, has the prospect of developing a therapeutic drug for p53 mutant tumors, and provides a new thought for realizing clinical treatment of p53 mutant tumors.
Description
Technical Field
The invention relates to the technical field of biological medicines, in particular to a small molecule polypeptide of a p53 mutant based on targeting degradation of a p53C176 palmitic acid modification site and application thereof.
Background
TP53 is an oncogene called "a keeper of genome", is located on human chromosome 17p13.1, totally encodes 393 amino acids, is a regulator in the cell growth cycle, and is involved in cell cycle regulation, DNA repair, cell differentiation, apoptosis, and the like. The p53 protein is a 53kDa protein encoded by TP53 gene, is a powerful tumor suppressor, and can inhibit tumor growth in various ways. As a transcription factor, p53 regulates the expression of target genes, promoting cell cycle arrest, apoptosis, DNA repair, etc. In addition, p53 may also exert antiproliferative effects by mechanisms other than transcription mechanisms. P53 is reported to affect almost all cellular compartments and organelles, including mitochondria, lysosomes, endoplasmic reticulum, and the like. In normal cells that are not under stress, the level of p53 is maintained at a low level by virtue of the in vivo E3 ubiquitin ligase MDM2 mediated protease degradation process.
When p53 protein is mutated, its cancer suppressing activity is impaired. Unlike other tumor suppressor genes, cancer-related p53 mutations are mainly missense mutations, resulting in single amino acid substitutions. In general, the mutant p53 thus produced accumulates in large amounts in cancer cells. In addition to the loss of binding to DNA and the ability to regulate transcription, which ultimately leads to the loss of cancer suppressing function, some mutant p53 proteins also acquire new functions, further promoting the development and progression of cancer. Studies have demonstrated that about 50% of human cancers have p53 protein mutations and that inhibitors targeting mutated p53 proteins are hot spots for the treatment of cancer. However, p53 has long been considered "non-patentable" because of its lack of typical drug target characteristics as a nuclear transcription factor. Nevertheless, a number of promising approaches to p 53-based therapies have emerged in recent years, most of which are currently represented by inhibitors that stabilize the wild-type p53 or restore the wild-type conformation of the mutant p53 protein and inhibit the interaction of MDM2 and p53 proteins. Although various therapeutic methods for p53 protein have been developed in recent years, a drug with ideal therapeutic effects has not been developed yet. Thus, the development of polypeptide inhibitors that target degradation of p53 mutants would provide an important reference for the clinical treatment of patients with p53 mutant cancers.
The complex function of p53 protein is closely related to its various post-translational modifications including phosphorylation, acetylation, and ubiquitination. Among these, palmitic acid modification is a form of modification that covalently links saturated fatty acids (palmitic acid) to proteins, and can affect subcellular localization, stability, and function of the proteins. The present team revealed for the first time that palmitic acid modifications of the p53 protein, which were found to occur at the positions p53C135, p53C176 and p53C275, were found to have an important role in regulating the subcellular nuclear localization of wild-type p53 (Tang J, et al oncogene.2021Sep;40 (35): 5416-5426.).
Disclosure of Invention
Therefore, the invention aims to provide the small molecular polypeptide of the targeted degradation p53 mutant based on the p53C176 palmitic acid modification site and the application thereof, wherein the small molecular polypeptide has an effective killing effect on p53 mutant tumors, can only kill tumor cells under the same effect, has no toxic or side effect basically on normal cells, has the advantages of high selectivity, weak toxic or side effect and the like, and has the prospect of developing into therapeutic drugs for p53 mutant tumors.
In order to achieve the above object, the present invention provides the following technical solutions:
The invention provides a small molecule polypeptide XY-0728 of a p53 mutant based on p53C176 palmitic acid modification site targeted degradation, wherein the sequence of the polypeptide XY-0728 is R8-TEVVRRCPHHERC.
The invention also provides application of the small molecule polypeptide XY-0728 of the targeted degradation p53 mutant in preparation of medicines for treating p53 mutant tumors.
Further, the p53 mutant tumor is breast cancer, esophageal cancer, lung cancer, pancreatic cancer, liver cancer and colon cancer.
The invention also provides a medicine for treating p53 mutant tumor, which contains the small molecule polypeptide XY-0728 of the targeted degradation p53 mutant.
Further, the p53 mutant tumor is breast cancer, esophageal cancer, lung cancer, pancreatic cancer, liver cancer and colon cancer.
The invention has the beneficial effects that the invention provides the small molecule polypeptide XY-0728 of the p53 mutant based on the p53C176 palmitic acid modification site and the application thereof, the sequence of the small molecule polypeptide XY-0728 is R8-TEVVRRCPHHERC, the small molecule polypeptide XY-0728 shows an effective killing effect on p53 mutant tumors, and can only kill tumor cells under the same effect, and the small molecule polypeptide XY-0728 has the advantages of basically no toxic or side effect on normal cells, high selectivity, weak toxic or side effect and the like, has the prospect of developing a therapeutic drug for p53 mutant tumors, and provides a new thought for realizing clinical treatment of p53 mutant tumors.
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FIG. 1 shows that XY-0728 can enter tumor cells rapidly, but not into normal immortalized epithelial cells 293T, as demonstrated by continuous monitoring of living cell dynamics.
FIG. 2 shows that XY-0728 can target p53 through immunofluorescence experiment, and block p53 from entering cell nucleus.
FIG. 3 shows that XY-0728 can degrade mutated p53 and cell nucleus in cells by immunofluorescence experiments.
FIG. 4 shows the result of CCK8 proliferation toxicity of polypeptide XY-0728 (μM) on different p53 mutant tumor cells.
FIG. 5 shows the result of CCK8 proliferation toxicity of polypeptide XY-072 (μM) 8 on BEAS-2B cells, 293T cells.
FIG. 6 shows the effect of XY-0728 on the clonogenic capacity of MB231 cells and KYSE150 cells.
FIG. 7 shows the effect of XY-0728 on the clonogenic capacity of H2122 cells and HT29 cells.
Fig. 8 is a photograph of a tumor of a mouse, wherein the sample was taken from day 15 after administration.
Fig. 9 is a graph showing tumor volume analysis results in mice, wherein samples were taken on day 15 after self-administration.
FIG. 10 is a line graph of the effect of polypeptide XY-0728 on tumor volume in mice.
FIG. 11 is a line graph showing the effect of polypeptide XY-0728 on mouse body weight.
Detailed Description
The technical scheme of the invention will be further described in detail below with reference to specific embodiments. It is to be understood that the following examples are illustrative only and are not to be construed as limiting the scope of the invention. All techniques implemented based on the above description of the invention are intended to be included within the scope of the invention. It should be noted that, in the examples of the present invention, the experimental materials from which the experimental materials are not specified are commercially available, and the experimental methods without specifying the specific conditions in the examples of the present invention are generally performed according to conventional experimental methods or according to the methods suggested by the manufacturers of the experimental materials. The p53 mutant tumor cells referred to in the present invention are PC9 cells (p 53 mutant lung cancer cell line), PC9/GR cells (PC 9 drug-resistant cell line), H2122 cells (p 53 mutant lung adenocarcinoma cell line), H1299 cells (p 53 mutant non-small cell lung cancer cell line), H1975 cells (p 53R273H mutant non-small cell lung cancer cell line), MB231 cells (p 53R280K mutant breast cancer cell line), SK-BR-3 cells (p 53R175H mutant breast cancer cell line), BT549 cells (p 53R249S mutant breast cancer cell line), KYSE150 cells (p 53R248Q mutant esophageal squamous carcinoma cell line), and HT29 cells (p 53R273H mutant colon cancer cell line).
EXAMPLE 1 dynamic continuous monitoring of viable cells confirmed that XY-0728 was able to enter tumor cells rapidly, while difficult to enter normal immortalized epithelial cells 293T
PC9 lung cancer cells expressing p53 mutation are selected, human embryo kidney cell strain 293T is used as control cells, after FITC marked XY-0728 (10 mu M) treatment is studied, a LEICA STELLARIS & STED laser confocal microscopic system is adopted for continuous living cell detection, wherein green is FITC marked XY-0728 for tracking polypeptide inhibitor, red is PI for tracking cell death, blue is DAPI for representing cell nuclei for staining, a bright field is externally applied, real-time monitoring is carried out, photos are taken every 5 minutes, a photo group picture is selected according to time points, and results are shown in figure 1, and the results prove that XY-0728 can rapidly enter tumor cells and is difficult to enter normal immortalized epithelial cells 293T.
Example 2 immunofluorescence experiments demonstrated that XY-0728 targets p53, blocking p53 entry into the nucleus
H1299 cells which do not express p53 per se were selected, wild-type p53 (p 53 WT) was transfected, and the effect on cancer cell localization after 6 hours of treatment with FITC-labeled XY-0728 (10. Mu.M) was investigated by immunofluorescence. The simple method is that firstly, the treated climbing-slice cells are washed with PBS for 3 times, each time for 5min.4% paraformaldehyde is fixed at room temperature for 30min, and washed with PBS 3 times for 5min each. Appropriate amount of 0.5% Triton-100 was added, and the slide was washed 3 times with PBS at room temperature for 10min. The immunostaining blocking solution is blocked for 1h at room temperature. Primary antibodies (anti-p 53, D01, sc-126, 1:200) were incubated overnight at 4 ℃. Rewarming for 1h at room temperature. PBS was used for 3 times, 5min each, and fluorescent secondary antibodies (anti-Mouse IgG 594,Jackson Immuno Research,111-585-003, 1:200) were incubated for 2h at room temperature (light-protected operation). PBS was used for 3 washes of 5min each. Directly adding a proper amount of DAPI for dyeing, and carrying out room temperature for 5min. DAPI was pipetted off and washed 3 times with PBS. The anti-quenching agent sealing tablet is observed under a confocal microscope, images are acquired, the results are shown in figure 2, and the results prove that XY-0728 can target p53 and block the p53 from entering the cell nucleus.
Example 3 immunofluorescence experiments demonstrated that XY-0728 degrades mutated p53 and nuclei in cells
Various p53 mutant cancer cells were selected, 293T was used as a control cell, and the effect of FITC-labeled XY-0728 (10. Mu.M) treatment for 6 hours on cancer cells was investigated by immunofluorescence. The results are shown in FIG. 3, which demonstrates that XY-0728 degrades mutated p53 and nuclei in cells, such as MB231(p53R280K)、NCIH1975(p53R273H)、KYSE150(p53R248Q)、Huh7(p53Y220H)、SK-BR-3(p53R175H)、BT549(p53R249S) and KYSE410 (p 53R 337C) cells, as described in example 2.
EXAMPLE 4 analysis of CCK8 proliferation toxicity of polypeptide XY-0728 on different P53 mutant tumor cells and Normal cells
The effect of the polypeptide XY-0728 on the proliferation of p53 mutant tumor cells, namely PC9 cells, PC9/GR cells, H2122 cells, H1299 cells, H1975 cells, MB231 cells, SK-BR-3 cells, BT549 cells, KYSE150 cells, HT29 cells and CCK8 proliferation of normal cells BEAS-2B cells and 293T cells, was examined at the cell level. Taking each cell in logarithmic growth phase, washing twice by PBS after removing the culture medium, centrifuging after pancreatin digestion to obtain cell sediment, and counting and paving the cell sediment in a 96-well plate. After the cells were attached, 2.5, 5,10, 20. Mu.M of the polypeptide XY-0728 was added to each cell, and OD450nm was measured at 0, 24, 48, 72h using CCK8 reagent as a control. The experimental results are shown in fig. 4-5, which show that the polypeptide XY-0728 has no effect on the growth of human embryonic kidney 293T cells and normal lung epithelial BEAS-2B cells (fig. 4), and the cell activities of p53 mutant tumor cells, namely PC9 cells, PC9/GR cells, H2122 cells, H1299 cells, H1975 cells, MB231 cells, SK-BR-3 cells, BT549 cells, KYSE150 cells and HT29 cells are remarkably reduced along with the increase of the concentration of the polypeptide XY-0728 (fig. 5). The growth of XY-0728 normal cells is not influenced, p53 mutant tumor cells such as PC9 cells, PC9/GR cells, H2122 cells, H1299 cells, H1975 cells, MB231 cells, SK-BR-3 cells, BT549 cells, KYSE150 cells and HT29 cells can be obviously inhibited, and the inhibition capacity is enhanced along with the increase of the concentration of the polypeptide XY-0728.
EXAMPLE 5 analysis of clonogenic Capacity of polypeptide XY-0728 to different p53 mutant tumor cells
The effect of the polypeptide XY-0728 on the clonogenic capacity of the different p53 mutant tumor cells MB231 cells, KYSE150 cells, H2122 cells, HT29 cells was examined at the cellular level. Taking each cell in logarithmic growth phase, washing twice by PBS after removing the culture medium, centrifuging after pancreatin digestion to obtain cell sediment, counting and spreading in a 24-well plate. After the cells are attached, polypeptide XY-0728 with the concentration of 2.5, 5 and 10 mu M is added into each cell respectively, and the culture medium is used as a control. After the cells grow to have obvious clone clusters, PBS is used for cleaning after the culture medium is abandoned, 4% paraformaldehyde is added for fixation for 30min, PBS is used for cleaning once after the fixation liquid is abandoned, crystal violet solution is added for dyeing, and photographing is carried out after the drying. The experimental results are shown in fig. 6-7, and the results show that the cloning capacity of p53 mutant tumor cells, namely MB231 cells, KYSE150 cells, H2122 cells and HT29 cells, is obviously reduced along with the increase of the concentration of the polypeptide XY-0728, which shows that the cloning capacity of the polypeptide XY-0728, namely MB231 cells, KYSE150 cells, H2122 cells and HT29, is obviously inhibited, and the inhibition capacity is enhanced along with the increase of the concentration of the polypeptide XY-0728.
EXAMPLE 6 analysis of tumor inhibiting Effect and weight Effect of polypeptide XY-0728 on MB231 cell and KYSE150 cell tumor-bearing mice
The breast cancer and esophageal cancer mice model was established by culturing MB231 and KYSE150 cells in large numbers, collecting cells in the logarithmic growth phase, removing the culture medium, washing twice with PBS, collecting cell pellets and counting. Subcutaneous injections of 0.1ml of approximately 2X 10 6 cells were performed in nude mice and the subcutaneous neoplasia was observed periodically. After confirming that the mice have tumor 5mm 2, the control group was injected with solvent DMSO (50 mg/kg) peritumorally and the experimental group was injected with polypeptide XY-0728 (50 mg/kg). Within 15 days, the experimental group was given 3 times cumulatively, the time was the first, third and fifth days, respectively. 15 days after administration, subjects were sacrificed, and the tumor condition was observed by photographing and the tumor volume was measured.
The tumor photographs of the mice are shown in fig. 8, 9 mice in each of the experimental group and the control group, and the tumor of the mice in the experimental group is significantly reduced compared with the tumor of the control group on the 15 th day after the sample is taken and self-administered. Mouse tumor volume analysis as shown in fig. 9, in the experimental group and the control group, each of 9 mice, in the KYSE150 tumor-bearing mice, the tumor-bearing volume of the 9 control group mice was gradually increased compared with the baseline tumor-bearing volume, and in the experimental group, the tumor-bearing volume of the rest mice was significantly reduced compared with the baseline volume except for the increase of the tumor-bearing volume of 1 mouse. In the MB231 tumor-bearing mice, the tumor volume of the mice in the control group is increased compared with the baseline during the experiment, the tumor volume of only 1 mouse in the experimental group is increased compared with the baseline, and the tumor volume of the other mice is reduced.
The tumor volume of the mice was measured periodically during the experiment, a line graph was drawn, and the experimental results are shown in fig. 10, in which the tumor volume of the mice in the experimental group was significantly reduced compared with the control group.
The body weight of the mice is measured periodically during the experiment period, and the experimental results are shown in fig. 11, and the results show that the body weights of the mice in the experimental group and the control group are not obviously different, which indicates that the polypeptide XY-0728 has little systemic toxicity to the mice and has no fundamental influence on the body weight matrix of the growth of the mice.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather to cover all modifications, equivalents, alternatives, and improvements that fall within the spirit and scope of the invention.
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