CN116173011A - Inhibitor for targeting SLC11A2 and application thereof - Google Patents
Inhibitor for targeting SLC11A2 and application thereof Download PDFInfo
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- CN116173011A CN116173011A CN202310167755.XA CN202310167755A CN116173011A CN 116173011 A CN116173011 A CN 116173011A CN 202310167755 A CN202310167755 A CN 202310167755A CN 116173011 A CN116173011 A CN 116173011A
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- liver cancer
- excavatolide
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- WOSKHXYHFSIKNG-UHFFFAOYSA-N lenvatinib Chemical compound C=12C=C(C(N)=O)C(OC)=CC2=NC=CC=1OC(C=C1Cl)=CC=C1NC(=O)NC1CC1 WOSKHXYHFSIKNG-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/10—Spiro-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Gastroenterology & Hepatology (AREA)
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
The invention belongs to the field of biological medicine, and particularly relates to a targeted SLC11A2 inhibitor and application thereof, wherein a CTD database is utilized to comprehensively search a drug target aiming at SLC11A2, and CCK8 and Transwell cell experiments are adopted to find that Excavatolide B has an inhibiting effect on liver cancer cells HEPG2 for the first time, and the SLC11A2 is proved to be a target for inhibiting the liver cancer cells HEPG2, so that the Excavatolide B has a great application prospect in the field of preparing drugs for inhibiting the liver cancer cells.
Description
Technical Field
The invention belongs to the field of biological medicine, and particularly relates to an inhibitor targeting SLC11A2 and application thereof.
Background
Liver cancer is one of the most common malignant tumors worldwide and is also the fourth leading cause of cancer-related death. Hepatocellular carcinoma (Hepatocellular carcinoma, HCC) is the main type of primary liver cancer, surgical resection is the main treatment for HCC, however, most liver cancer patients are diagnosed in the late stage due to rapid growth of tumor and manifestation of late stage symptoms, and do not meet the conditions of surgical treatment. The median survival of patients with advanced HCC is about 9 months, the overall survival of 5 years is only 10% and the prognosis is poor. Sorafenib, lenvatinib and regorafenib are currently the standard treatment for advanced HCC, but treatment options for advanced HCC patients are still very limited and current drugs have low clinical efficacy for HCC patients. Research on HCC-related targeted drugs is of great importance in improving treatment of liver cancer.
SLC11A2, also known as divalent metal transporter 1 (DMT 1), belongs to a soluble carrier family member, is a proton-coupled transmembrane metal ion transporter in mammals that mediates ferrous and heavy metal transport in systemic iron homeostasis. Iron plays an indispensable role in the tumorigenesis and progression process, and the mechanism involved in regulating and controlling iron steady state changes correspondingly so as to adapt to the metabolic level of the iron and maintain the activity of tumor cells. Clinically, SLC11A2 is mostly in negative correlation with liver cancer differentiated tissues, and no drug targeting SLC11A2 to inhibit liver cancer cells exists in the prior art.
Disclosure of Invention
Aiming at the problems existing in the prior art, the invention aims to provide a targeted SLC11A2 inhibitor and application thereof, and the invention discovers that Excavalide B has an inhibiting effect on liver cancer cell HEPG2 for the first time, and proves that SLC11A2 is a target for inhibiting liver cancer cell HEPG2, and has a great application prospect in the field of medicines for inhibiting liver cancer cells.
Based on the above purpose, the technical scheme adopted by the invention is as follows:
in a first aspect, the invention provides the use of excavatide B in targeted inhibition of SLC11A2, said excavatide B having the chemical structure:
in a second aspect, the invention provides an inhibitor targeted to inhibit SLC11A2, the inhibitor comprising Excavatolide B.
In a third aspect, the invention provides an application of Excavatolide B in a drug for targeted inhibition of liver cancer cell HEPG2 proliferation.
In a fourth aspect, the invention provides an application of Excavatolide B in preparing a medicament for treating liver cancer.
In a fifth aspect, the present invention provides a drug targeted to inhibit HEPG2 proliferation of liver cancer cells, the drug comprising excabaltolide B as an active ingredient.
In a sixth aspect, the invention provides a pharmaceutical preparation for targeted inhibition of liver cancer cell HEPG2 proliferation, wherein the pharmaceutical preparation is prepared by adding pharmaceutically acceptable additives or/and excipients or/and carriers into an Excavatolide B serving as an active ingredient.
In a seventh aspect, the present invention provides a medicament for treating liver cancer, comprising Excavatolide B as an active ingredient.
In an eighth aspect, the invention provides a pharmaceutical preparation for treating liver cancer, which is prepared by adding pharmaceutically acceptable additives or/and excipients or/and carriers into an Excavatolide B serving as an active ingredient.
Preferably, the medicament or the pharmaceutical preparation is a tablet, a granule or a liquid preparation.
Compared with the prior art, the invention has the following beneficial effects:
according to the invention, a drug target aiming at SLC11A2 is screened based on a CTD database, and the Excavatolide B is found to have an inhibiting effect on liver cancer cells HEPG2 for the first time by adopting CCK8 and Transwell cell experiments, and the SLC11A2 is proved to be a target for inhibiting HEPG2, so that the Excavatolide B has a great application prospect in the field of preparing medicaments for treating liver cancer.
Drawings
FIG. 1 is a chemical formula of Excavatolide B;
FIG. 2 is a graph showing the effect of CCK8 detection on HEPG cell proliferation;
FIG. 3 is a graph showing the effect of Transwell detection on HEPG cell invasion;
FIG. 4 is a graph showing the effect of Transwell detection on HEPG2 cell invasion.
Detailed Description
For a better description of the objects, technical solutions and advantages of the present invention, the present invention will be further described with reference to the following specific examples. It will be appreciated by persons skilled in the art that the specific embodiments described herein are for purposes of illustration only and are not intended to be limiting.
The test methods used in the examples are conventional methods unless otherwise specified; the materials, reagents and the like used, unless otherwise specified, are all commercially available. The cell sources used for the experiments were as follows: HEPG2-shNC and HEPG2-shSLC11A2 cells were constructed from HEPG2 cell lines by laboratory. Excavatolide B was purchased from sigma and dissolved in DMSO.
Example 1
According to the invention, drug-gene association relation search analysis is performed based on a Comparative Toxicogenomics Database (CTD, version 2019.6) database, and information such as a drug target list, a drug CAS number, a target Entrez ID, a target belonged species, an action type, a reference and the like aiming at an iron death related gene SLC11A2 for promoting liver cancer metastasis is screened out. Further, CCK8 and Transwell cell experiments are adopted to examine the influence of various drugs on proliferation and invasion of liver cancer HEPG2 cells and the targeting effect of SLC11A2, and finally, a compound Expavatolide B (the chemical structure of which is shown in figure 1) with the inhibiting effect on liver cancer HEPG2 cells is screened out, and the specific experimental method is as follows:
(1) Cell culture and treatment
The cell line obtained was cultured in a modified 1640 medium (HyClone, sh30809.01 b). The medium consisted of 10% strength fetal bovine serum (Gibco, 1027-106) and diabodies (containing penicillin 100U/ml and streptomycin 0.1mg/ml, produced by TBD under the trade designation PS2004 HY). Cell culture conditions were 5% CO 2 And 37 ℃, changing the culture medium every three days.
(2) Database analysis
The method is characterized in that an online site four general databases Comparative Toxicogenomics Database (CTD, version 2019.6) are adopted to search the drug-gene relationship, and information such as a drug target list, a drug CAS number, a target Entrez ID, a target belonging species, an action type, a reference and the like of the gene appears when the iron death related gene SLC11A2 which is screened in vivo by utilizing a CRISPR library in the early stage and promotes liver cancer metastasis is input.
(3) CCK8 experiment
Cells with good growth status were digested with a solution of trypsin-EDTA (BIOSHARP, WH 0518) and counted; cell suspensions (200. Mu.L/well) were prepared according to the count and inoculum size (8000/well); the prepared cell suspension was inoculated into a 96-well plate, and the culture plate was placed in an incubator (37 ℃,5% CO) 2 ) Pre-incubation for 24h, control HEPG2-shNC and HEPG2-shSLC11A2 cells (addition 10uM Excavatolide B) were incubated in incubator for 48h (grouping and drug treatment are shown in the following table); add 20. Mu.L of CCK8 solution (Biyun Tian, C0039) to each well; incubating the plates in the incubator for 2 hours; measuring absorbance at 450nm with a microplate reader (Thermo, multiskoun GO); the experimental results are shown in table 1 and fig. 2. The result shows that the Excavatolide B targets on SLC11A2, thereby inhibiting proliferation of liver cancer cells HEPG 2.
TABLE 1CCK8 detection of Effect on liver cancer cell proliferation
| Group of | Treatment mode | N | OD value ± standard deviation |
| NC | - | 3.000 | 1.169±0.013 |
| 1 | sh-SLC11A2+Excavatolide B | 3.000 | 0.746±0.005 |
| 2 | Excavatolide B | 3.000 | 1.036±0.057* |
(4) Transwell experiment
Taking HEPG2-shNC and HEPG2-shSLC11A2 liver cancer cell lines, digesting cells with a trypsin-EDTA solution, centrifuging after stopping digestion, discarding culture solution, washing 1-2 times with PBS, and re-suspending with a serum-free culture medium to prepare a cell suspension (drug treatment group +10uMExcavatolide B); inoculation of 8X 10 4 Cells were supplemented in the upper chamber and the lower chamber with 500. Mu.L of complete medium (each group containing 10uMExcavatolide B, control group NC without drug), and the plates were placed in an incubator for cultivation (37 ℃,5% CO) 2 ) 48h; washing cells with PBS buffer solution for 1-2 times, absorbing residual liquid, adding paraformaldehyde for fixing for 20 min, discarding the fixing solution, adding 0.1% crystal violet dye solution (BIOSHARP, amresco 0528), dyeing for 10-20 min, discarding the dyeing solution, washing the dyeing solution with PBS, and wiping the upper cell with medical cotton swab; cutting off the film of the chamber by a blade or a needle, placing the film on a glass slide, and dripping neutral gum to cover the glass slide; observing the dyeing result under a microscope and photographing; cell counts, 3 fields of view were randomly selected under a 400-fold microscope to observe cells, counts. The experimental results are shown in fig. 3, fig. 4 and table 2. The results indicate that Excavatolide B targets SLC11A2, thereby inhibiting HEPG2 invasion.
TABLE 2Transwell detection of Effect on cell invasion
| Group of | Treatment mode | N | OD value ± standard deviation |
| NC | - | 3.000 | 124.333±2.517 |
| 1 | sh-SLC11A2+Excavatolide B | 3.000 | 26.000±1.732 |
| 2 | Excavatolide B | 3.000 | 34.667±0.577* |
Finally, it should be noted that the above embodiments are only for illustrating the technical solution of the present invention and not for limiting the scope of the present invention, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that the technical solution of the present invention may be modified or substituted equally without departing from the spirit and scope of the technical solution of the present invention.
Claims (9)
- Use of Excavatolide B for targeted inhibition of SLC11A2, wherein the chemical structure of Excavatolide B is as follows:
- 2. an inhibitor that targets SLC11A2, comprising the exact B of claim 1.
- 3. Use of the Excavatolide B of claim 1 in a medicament for targeted inhibition of liver cancer cell HEPG2 proliferation.
- 4. The use of the Excavatolide B of claim 1 in the preparation of a medicament for treating liver cancer.
- 5. A drug targeted to inhibit HEPG2 proliferation of liver cancer cells, comprising the extravatolide B of claim 1 as an active ingredient.
- 6. A pharmaceutical preparation for targeted inhibition of liver cancer cell HEPG2 proliferation, which is characterized in that the pharmaceutical preparation is prepared by adding a pharmaceutically acceptable additive or/and excipient or/and carrier into the Excavatolide B as an active ingredient in claim 1.
- 7. A medicament for treating liver cancer, which comprises the exact B of claim 1 as an active ingredient.
- 8. A pharmaceutical preparation for treating liver cancer, which is characterized in that the pharmaceutical preparation is prepared by adding pharmaceutically acceptable additives or/and excipients or/and carriers into the Excavatolide B as an active ingredient in claim 1.
- 9. A medicament or pharmaceutical formulation according to any one of claims 5 to 8, wherein the medicament or pharmaceutical formulation is a tablet, granule or liquid formulation.
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| CN202310167755.XA CN116173011B (en) | 2023-02-23 | 2023-02-23 | Inhibitor for targeting SLC11A2 and application thereof |
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| CN116173011B CN116173011B (en) | 2024-09-27 |
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| KR20180121771A (en) * | 2018-10-30 | 2018-11-08 | 주식회사 하임바이오 | Pharmaceutical composition for preventing or treating cancer |
| CN109157533A (en) * | 2018-10-29 | 2019-01-08 | 上海市浦东新区传染病医院 | Application of the atractylone in preparation anti-liver cancer and anti-molecular target drug |
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|---|---|---|---|---|
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