CN116211866A - Application of K279-0738 in preparation of medicines for treating and/or preventing tumors - Google Patents
Application of K279-0738 in preparation of medicines for treating and/or preventing tumors Download PDFInfo
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- CN116211866A CN116211866A CN202310104768.2A CN202310104768A CN116211866A CN 116211866 A CN116211866 A CN 116211866A CN 202310104768 A CN202310104768 A CN 202310104768A CN 116211866 A CN116211866 A CN 116211866A
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- A61P35/04—Antineoplastic agents specific for metastasis
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Abstract
The invention discloses an application of K279-0738 in preparing a medicine for treating and/or preventing tumor, belonging to the technical field of biological medicine. The structural formula of the K279-0738 is shown as the formula (I), and the effective concentration of the K279-0738 is 2.5-5 mu M. The invention discovers that the small molecular compound K279-0738 can inhibit the invasion and metastasis of esophageal cancer for the first time, and particularly inhibits the invasion and metastasis of esophageal cancer by targeting KCTD4. The small molecular compound K279-0738 has certain safety as a potential anti-tumor drug, and has great advantages in drug effect and price.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to application of K279-0738 in preparation of medicines for treating and/or preventing tumors.
Background
Esophageal cancer is one of the most deadly cancers in the world, with both morbidity and mortality remaining in the first ten days of china, with 90% of mortality being caused by tumor metastasis. Tumor metastasis procedures are complex and difficult to study, particularly with respect to genes associated with metastasis in Esophageal Squamous Cell Carcinoma (ESCC), with little information and functional verification. Thus, a comprehensive investigation of key drivers and signaling pathways regulating cancer metastasis would provide new clues for cancer treatment.
Surgery, radiation therapy, chemotherapy and molecular targeted drugs are several major approaches to the treatment of esophageal cancer. Wherein surgery and radiotherapy are topical treatments and chemotherapy and molecular targeted drug treatments are systemic treatments. However, the commonly used anticancer drugs often have certain toxic and side effects, and the tolerance in the chemotherapy process leads to postoperative recurrence and poor prognosis of patients, and the treatment difficulty is increased. The small molecular medicine can specifically block the signal transmission path necessary for the growth and proliferation of tumor, so as to achieve the aim of treatment. The small molecule inhibitor has the following advantages: (1) high oral bioavailability; (2) The physiological barrier has good permeability, can penetrate through cell membranes and acts on intracellular targets; (3) lower cost. Therefore, the development of the small molecular compound as a medicament for treating cancers has great advantages in the medicament effect and the price.
K279-0738 (N- (4-methoxybenzoyl) -3- {5- [ (3-Nitrobenzoyl) Thio ] -3-Oxo-2, 3-dihydrooimidazo [1,2-C ] Quinazolin-2-Yl } Propanamide) is a small molecule compound of the formula:
there is no application of K279-0738 in inhibiting cancer cells, especially in inhibiting invasion and metastasis of cancer cells.
Disclosure of Invention
The primary aim of the invention is to overcome the defects and shortcomings of the prior art and provide the application of K279-0738 in preparing medicines for treating and/or preventing esophageal cancer.
The above object of the present invention is achieved by the following technical solutions:
the application of K279-0738 in preparing a medicament for treating and/or preventing esophageal cancer is characterized in that the structural formula of K279-0738 is shown as the formula (I):
further, the effective concentration of K279-0738 is 2.5-5 mu M.
Further, the medicine for treating and/or preventing the esophageal cancer is a medicine capable of inhibiting invasion and/or metastasis of esophageal cancer cells.
Further, the esophageal cancer includes, but is not limited to, esophageal squamous carcinoma.
Further, K279-0738 inhibits invasion and/or metastasis of esophageal cancer by targeting KCTD4. The nucleotide sequence encoding KCTD4 is shown as the Gene sequence accession number 386618 in NCBI Gene bank database.
A medicament for treating and/or preventing esophageal cancer, comprising K279-0738, wherein the structural formula of the K279-0738 is shown as formula (I):
further, the medicament for treating and/or preventing the esophageal cancer further comprises pharmaceutically acceptable auxiliary materials.
Further, the pharmaceutically acceptable auxiliary materials are at least one of sustained release agents, excipients, fillers, adhesives, wetting agents, disintegrating agents, absorption promoters, adsorption carriers, surfactants and lubricants.
Further, the administration mode of the medicine for treating and/or preventing esophageal cancer is at least one of oral administration, gastric lavage administration and injection administration.
Compared with the prior art, the invention has the following advantages and effects:
the invention discovers that the small molecular compound K279-0738 can inhibit invasion and metastasis of esophageal cancer for the first time, and particularly inhibits invasion and metastasis of esophageal cancer by targeting KCTD4. The small molecular compound K279-0738 has certain safety as a potential anti-tumor drug and has great advantages in drug effect and price.
Drawings
FIG. 1 is a structural diagram of K279-0738.
FIG. 2 is a graph showing the results of the research on the invasion ability of KCTD4 gene to human esophageal squamous carcinoma luciferase-labeled cells KYSE150-LUC and human esophageal squamous carcinoma cells KYSE 410.
FIG. 3 is a graph showing the result of the research on the lung metastasis capability of KCTD4 gene on human esophageal squamous carcinoma luciferase-labeled cells KYSE 150-LUC.
FIG. 4 is a graph showing the results of a study of the effect of different concentrations of K279-0738 on the invasive capacity of esophageal squamous carcinoma cells.
FIG. 5 is a graph showing the fluorescence detection results of the study of the influence of K279-0738 on the lung metastasis capacity of esophageal squamous carcinoma cells.
FIG. 6 is a graph showing the results of immunohistochemical analysis of the effect of K279-0738 on liver, lung, kidney and spleen functions in mice.
Detailed Description
The present invention will be described in further detail with reference to examples and drawings, but embodiments of the present invention are not limited thereto.
K279-0738 is synthesized by Shanghai Tao Su Biochemical technology Co., ltd and has the following structural formula:
human esophageal squamous carcinoma cell KYSE150, human esophageal squamous carcinoma cell KYSE410, human esophageal squamous carcinoma cell KYSE270 were purchased from German microorganisms and cell culture Co., ltd; LB medium was purchased from Biotechnology (Shanghai) Inc., 0.25% of pancreatin was purchased from Gibco, U.S.A. Experimental female mice (NOD-SCID) were purchased from Jiangsu Jiugang Biotech Co.
Human esophageal squamous carcinoma luciferase-labeled cells KYSE150-LUC have been described in the literature "Wen xu et al direct Targeting of CREB1 with Imperatorin Inhibits TGF. Beta.2-ERK Signaling to Suppress Esophageal Cancer Metastasis, advanced Science 2020.DOI:10.1002/advs.202000925 ".
KYSE150-LUC-LM3 cell construction method: 0.25% pancreatin the human esophageal squamous carcinoma luciferase-tagged cells KYSE150-LUC were digested into single cells, 10 6 The luciferase-labeled cells KYSE150-LUC of the individual esophageal squamous carcinoma were resuspended in 100. Mu.L PBS buffer and injected into the tail veinIn the body of a mouse; after 5 to 6 weeks of feeding, D-Luciferin (purchased from GOLDBIO corporation) was intraperitoneally injected for in vivo fluorescence photography; dissecting the mice with lung metastasis, and taking out the lungs with KYSE150-LUC cell metastasis; cutting the lung into meat paste, and re-suspending the culture medium; after one week of standing, PSB buffer was washed twice, and Blastidin (5. Mu.g/mL, purchased from Shanghai Biyundian Biotechnology Co., ltd.) was added and screened for one week to no cell death, which was KYSE150-LUC-LM1. Then 0.25% of pancreatin digests human esophageal squamous carcinoma luciferase-labeled cells KYSE150-LUC-LM1 into single cells, 10 6 The individual esophageal squamous carcinoma luciferase-labeled cells KYSE150-LUC-LM1 were resuspended in 100 μLPBS buffer and injected into mice by tail vein; after 5 to 6 weeks of feeding, D-Luciferin (purchased from GOLDBIO corporation) was intraperitoneally injected for in vivo fluorescence photography; dissecting the mice with lung metastasis, and taking out the lungs with KYSE150-LUC-LM1 cell metastasis; the lung is minced to meat paste shape, and the culture medium is resuspended; after one week of standing, PSB buffer was washed twice, and Blastidin (5. Mu.g/mL, purchased from Shanghai Biyundian Biotechnology Co., ltd.) was added and screened for one week to no cell death, which was KYSE150-LUC-LM2. And circulating for 3 times to obtain KYSE150-LUC-LM3 cells.
Construction methods of human esophageal squamous carcinoma luciferase marker cells KYSE150-LUC (namely KYSE150-LUC-KCTD4 cells) with stable and over-expressed KCTD4 genes and human esophageal squamous carcinoma cells KYSE410 (namely KYSE410-KCT D4 cells) with stable and over-expressed KCTD4 genes: the KCTD4 Gene (Gene ID: 386618) was constructed on a pTSB-CMV-MCS-SBP-3Flag-co pGFP-F2A-Puror expression vector (TranSheepBio) to give a KCTD4 eukaryotic expression plasmid (entrusted to construction of Shanghai right-of-the-eye Biotechnology Co., ltd.). The constructed plasmid is transformed into 293T cells, and the 293T cells with good growth state are paved on a 6-well plate after being digested. And (4) performing KCTD4 eukaryotic expression plasmid transfection when the cells grow to 50% -60%. After 24 hours, cells were changed after 48 hours, and the supernatant was collected. The supernatant was centrifuged and filtered with a 0.45 μm filter. Adding the supernatant into KYSE150-LUC cells and human esophageal cancer KYSE410 cells respectively, transferring the cells from a six-hole plate to a small bottle after 48 hours of infection, adding puromycin (purchased from Sigma-Aldrich company) with the working concentration of 1 mug/mL for screening after adherence, stopping adding medicines when the cells do not die any more after 1-2 weeks, thus obtaining KCTD4 gene-stably overexpressed human esophageal squamous carcinoma luciferase labeled cells KYSE150-LUC (namely KYSE150-LUC-KCTD4 cells) and KCTD4 gene-stably overexpressed human esophageal squamous carcinoma cells KYSE410 (namely KYSE410-LUC-KCTD4 cells), and identifying that the cells can overexpress KCTD4 through Western blot.
Example 1: KCTD4 gene can improve the metastatic invasion capacity of human esophageal squamous carcinoma cells
1. KCTD4 stable overexpression was performed on esophageal squamous carcinoma cells, and then cell invasiveness was examined by an investment test and an in vivo mouse test.
(1) Cell Invasion (Invision) experiment
1) Cell treatment: 100. Mu.L of 5% matrigel was added to the clean invasion chamber and placed in an incubator at 37℃for 30 minutes.
2) Paving cells: human esophageal squamous carcinoma luciferase-labeled cells KYSE150-LUC (namely KYSE150-LUC-KCTD4 cells) with stable and over-expressed KCTD4 genes and human esophageal squamous carcinoma cells KYSE410 (namely KYSE410-KCTD4 cells) with stable and over-expressed KCTD4 genes are digested into suspended single cells by 0.25% trypsin, after counting, 50 ten thousand KYSE150-LUC-KCTD4 cells and 20 ten thousand KYSE410-KCTD4 cells are respectively added into the upper layer of the cell, 500 mu L of complete culture medium is added into the lower layer, and at 37 ℃ and 5% CO 2 Culturing for 24 hours under the condition. Meanwhile, the experiment is carried out by taking human esophageal squamous carcinoma luciferase labeled cells KYSE150-LUC and human esophageal squamous carcinoma cells KYSE410 as controls.
3) Crystal violet staining: taking out the cell, washing twice with PBS buffer (pH 7.4, purchased from Sigma-Aldrich Co., ltd.; same below), adding 500. Mu.L of methanol into the lower cell, fixing for 10min, sucking off the methanol, adding 0.2% crystal violet for dyeing for 10min, sucking off the crystal violet, washing off residual crystal violet with clear water, and photographing after air drying.
(2) In vivo experiments
12 female mice (NOD-SCID) of 6 weeks of age, 6 control and 6 experimental groups were selected to construct tumor metastasis models.
(1) 0.25% pancreatin marks the human esophageal squamous carcinoma luciferase-tagged cells KYSE150-LUC and respectivelyKYSE150-LUC-KCTD4 cells were digested into single cells. Respectively will 10 6 Individual esophageal squamous carcinoma luciferase-labeled cells KYSE150-LUC and KYSE150-LUC-KCTD4 esophageal squamous carcinoma cells were resuspended in 100 μl PBS buffer.
(2) The method comprises the steps of (1) anaesthetizing a mouse before the tail vein experiment of the animal, and evaluating the anaesthetic degree through painless and painful stimulation to determine that the mouse is in an anaesthetic state;
(3) Mice were injected tail vein with 25G needle microinjector resuspended cells for a total of 12.
After 5 to 6 weeks of feeding, D-Luciferin (available from GOLDBIO) was intraperitoneally injected, and in vivo fluorescence photographing was performed to observe lung metastasis of cancer cells.
The results are shown in fig. 2 and 3. As can be seen from the in vitro experiment results of FIG. 2, the KCTD4 gene can improve the invasion capacity of human esophageal squamous carcinoma luciferase-labeled cells KYSE150-LUC and human esophageal squamous carcinoma cells KYSE 410-LUC. From the in vivo experimental results of FIG. 3, it is understood that the KCTD4 gene can promote KYSE150-LUC lung metastasis of human esophageal squamous carcinoma luciferase-labeled cells in mice.
Example 2: k279-0738 functional verification
(1) Invitation test
Esophageal squamous carcinoma cells are treated with K279-0738 with different concentrations, then the invasion capacity of the esophageal squamous carcinoma cells is detected, and the influence of the K279-0738 with different concentrations on the invasion capacity of the esophageal squamous carcinoma cells is studied.
1) Cell treatment: 100. Mu.L of 5% matrigel was added to the clean invasion chamber and placed in an incubator at 37℃for 30 minutes.
2) Paving cells: human esophageal squamous carcinoma cells KYSE150-LUC-LM3 and KYSE270 cells with high invasiveness are digested into suspended single cells by 0.25% trypsin, 50 ten thousand KYSE150-LUC-LM3 cells and 20 ten thousand KYSE270 cells are added into the upper layer of each cell after counting, and K279-0738 with different concentrations (the final concentration is 0,2.5 mu M and 5 mu M respectively) are added; adding 500 μl of complete medium into the lower layer, and heating at 37deg.C with 5% CO 2 Culturing for 24 hours under the condition.
3) Crystal violet staining: taking out the cell, washing twice with PBS buffer solution, adding 500 μl of methanol into the lower cell, fixing for 10min, sucking off methanol, adding 0.2% crystal violet for dyeing for 10min, sucking off crystal violet, washing off residual crystal violet with clear water, air drying, and photographing.
As can be seen from the results of the in vitro test in FIG. 4, the invasive capacity of esophageal squamous carcinoma cells decreased with increasing concentration of K279-0738.
(2) In vivo experiments
Tumor metastasis models were constructed by selecting 6 of 18 6 week old female mice (NOD-SCID) control groups 6 and 12 experimental groups.
1) 0.25% of pancreatin digests human esophageal squamous carcinoma luciferase-tagged cells KYSE150-LUC-LM3 cells into single cells; will 10 6 Individual esophageal squamous carcinoma luciferase-labeled cells KYSE150-LUC-LM3 esophageal squamous carcinoma cells were resuspended in 100 μl PBS buffer.
2) The method comprises the steps of (1) anaesthetizing a mouse before an experiment, and evaluating the anaesthetic degree through painless and painful stimulation to determine that the mouse is in an anaesthetic state;
3) Mice were injected tail vein with 25G needle microinjector resuspended cells for a total of 18.
4) K279-0738 treatment: mice were dosed by gavage after 3 weeks of tail vein injection with esophageal squamous carcinoma cells KYSE 150-LUC-LM. K279-0738 was dissolved in PBS buffer, and each group of mice was treated with the drug at a concentration of 0mg/kg (i.e., control group), 2.5mg/kg (i.e., test group 1), and 5mg/kg (i.e., test group 2) each 6 animals, once a week. After 5 to 6 weeks, D-Luciferin (purchased from GOLDBIO) was injected intraperitoneally, and in vivo fluorescence photographing was performed to observe the metastasis of cancer cells.
From the in vivo results of FIG. 5, it can be seen that the bioluminescence of the lungs of the K279-0738 treated mice was reduced. Bioluminescence is generated by enzymatic reaction of luciferases in KYSE150-LUC-LM3 cells of esophageal squamous carcinoma with D-luciferases in body fluid, and the intensity of fluorescence reflects the density of KYSE150-LUC-LM3 cells. Thus, the number of lung metastases of esophageal cancer cells in the K279-0738 treated group (i.e., experimental group) was significantly less than in the control group.
The mice treated with K279-0738 (2.5 mg/kg and 5 mg/kg) were taken out of the liver, lung, kidney and spleen for immunohistochemistry, and the results show (as shown in FIG. 6) that K279-0738 has no effect on liver, lung, kidney and spleen functions of the mice.
The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.
Claims (9)
- The application of K279-0738 in preparing a medicament for treating and/or preventing esophageal cancer is characterized in that: the structural formula of K279-0738 is shown as formula (I):
- 2. the use of K279-0738 according to claim 1 for the manufacture of a medicament for the treatment and/or prophylaxis of oesophageal cancer, characterized in that:the effective concentration of K279-0738 is 2.5-5 mu M.
- 3. Use of K279-0738 according to claim 1 or 2 for the manufacture of a medicament for the treatment and/or prevention of oesophageal cancer, characterized in that:the medicine for treating and/or preventing the esophageal cancer is a medicine capable of inhibiting invasion and/or metastasis of esophageal cancer cells.
- 4. Use of K279-0738 according to claim 1 or 2 for the manufacture of a medicament for the treatment and/or prevention of oesophageal cancer, characterized in that:the esophageal cancer is esophageal squamous cell carcinoma.
- 5. Use of K279-0738 according to claim 1 or 2 for the manufacture of a medicament for the treatment and/or prevention of oesophageal cancer, characterized in that:the K279-0738 inhibits invasion and/or metastasis of esophageal cancer by targeting KCTD4 gene.
- 6. A medicament for the treatment and/or prophylaxis of esophageal cancer, characterized in that: comprises K279-0738, wherein the structural formula of the K279-0738 is shown as the formula (I):
- 7. the medicament for the treatment and/or prevention of esophageal cancer according to claim 6, wherein:the medicine for treating and/or preventing esophageal cancer also comprises pharmaceutically acceptable auxiliary materials.
- 8. The medicament for the treatment and/or prevention of esophageal cancer according to claim 7, wherein:the pharmaceutically acceptable auxiliary materials are at least one of sustained release agent, excipient, filler, adhesive, wetting agent, disintegrating agent, absorption promoter, adsorption carrier, surfactant and lubricant.
- 9. A medicament for the treatment and/or prophylaxis of esophageal cancer according to any one of claims 6-8, wherein:the administration mode of the medicine for treating and/or preventing the esophageal cancer is oral administration, gastric lavage administration or injection administration.
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